SIGNALING PATHWAYS THAT DEPEND ON REGULATED PROTEOLYSIS

In addition to the signaling pathways that we have already discussed

there is another group of signaling pathways that are dependent on

REGULATED PROTEOLYSIS1048707 These pathways are highly conserved in animal evolution andused repeatedly to regulate events that occur during

development and also to some extent in adult tissues

1 NOTCH RECEPTOR PATHWAY

bull Signaling involving the Notch receptor is likely the most widelyused pathway during development

bull The general role of Notch pathways is to control cell fate choicesduring development by amplifying and consolidating moleculardifferences between adjacent cells

bull Lateral inhibition is a process that occurs during development inwhich a cell will signal to its neighboring cells not to develop in thesame wayo Lateral inhibition is important in nervous systemdevelopment in Drosophilia as a

committed nerve cell willsignal neighboring cells to not develop into a nerve cell butinstead become epidermal cells bull Lateral inhibition involves contact‐dependent signaling that is

mediated by the presence of cell‐surface signal protein calledDelta on the developing (eg nerve) cello Delta binds to Notch on surrounding cells and signals themto not become the same type of cell as the

Delta‐expressing cell1048707 Both Delta and Notch are single‐pass transmembrane proteins and both requireproteolytic processing to functionbull While it is not clear what function proteolytic cleavage of Delta plays it is clear

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

there is another group of signaling pathways that are dependent on

REGULATED PROTEOLYSIS1048707 These pathways are highly conserved in animal evolution andused repeatedly to regulate events that occur during

development and also to some extent in adult tissues

1 NOTCH RECEPTOR PATHWAY

bull Signaling involving the Notch receptor is likely the most widelyused pathway during development

bull The general role of Notch pathways is to control cell fate choicesduring development by amplifying and consolidating moleculardifferences between adjacent cells

bull Lateral inhibition is a process that occurs during development inwhich a cell will signal to its neighboring cells not to develop in thesame wayo Lateral inhibition is important in nervous systemdevelopment in Drosophilia as a

committed nerve cell willsignal neighboring cells to not develop into a nerve cell butinstead become epidermal cells bull Lateral inhibition involves contact‐dependent signaling that is

mediated by the presence of cell‐surface signal protein calledDelta on the developing (eg nerve) cello Delta binds to Notch on surrounding cells and signals themto not become the same type of cell as the

Delta‐expressing cell1048707 Both Delta and Notch are single‐pass transmembrane proteins and both requireproteolytic processing to functionbull While it is not clear what function proteolytic cleavage of Delta plays it is clear

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

development and also to some extent in adult tissues

1 NOTCH RECEPTOR PATHWAY

bull Signaling involving the Notch receptor is likely the most widelyused pathway during development

bull The general role of Notch pathways is to control cell fate choicesduring development by amplifying and consolidating moleculardifferences between adjacent cells

bull Lateral inhibition is a process that occurs during development inwhich a cell will signal to its neighboring cells not to develop in thesame wayo Lateral inhibition is important in nervous systemdevelopment in Drosophilia as a

committed nerve cell willsignal neighboring cells to not develop into a nerve cell butinstead become epidermal cells bull Lateral inhibition involves contact‐dependent signaling that is

mediated by the presence of cell‐surface signal protein calledDelta on the developing (eg nerve) cello Delta binds to Notch on surrounding cells and signals themto not become the same type of cell as the

Delta‐expressing cell1048707 Both Delta and Notch are single‐pass transmembrane proteins and both requireproteolytic processing to functionbull While it is not clear what function proteolytic cleavage of Delta plays it is clear

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

bull The general role of Notch pathways is to control cell fate choicesduring development by amplifying and consolidating moleculardifferences between adjacent cells

bull Lateral inhibition is a process that occurs during development inwhich a cell will signal to its neighboring cells not to develop in thesame wayo Lateral inhibition is important in nervous systemdevelopment in Drosophilia as a

committed nerve cell willsignal neighboring cells to not develop into a nerve cell butinstead become epidermal cells bull Lateral inhibition involves contact‐dependent signaling that is

mediated by the presence of cell‐surface signal protein calledDelta on the developing (eg nerve) cello Delta binds to Notch on surrounding cells and signals themto not become the same type of cell as the

Delta‐expressing cell1048707 Both Delta and Notch are single‐pass transmembrane proteins and both requireproteolytic processing to functionbull While it is not clear what function proteolytic cleavage of Delta plays it is clear

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

bull Lateral inhibition is a process that occurs during development inwhich a cell will signal to its neighboring cells not to develop in thesame wayo Lateral inhibition is important in nervous systemdevelopment in Drosophilia as a

committed nerve cell willsignal neighboring cells to not develop into a nerve cell butinstead become epidermal cells bull Lateral inhibition involves contact‐dependent signaling that is

mediated by the presence of cell‐surface signal protein calledDelta on the developing (eg nerve) cello Delta binds to Notch on surrounding cells and signals themto not become the same type of cell as the

Delta‐expressing cell1048707 Both Delta and Notch are single‐pass transmembrane proteins and both requireproteolytic processing to functionbull While it is not clear what function proteolytic cleavage of Delta plays it is clear

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

committed nerve cell willsignal neighboring cells to not develop into a nerve cell butinstead become epidermal cells bull Lateral inhibition involves contact‐dependent signaling that is

mediated by the presence of cell‐surface signal protein calledDelta on the developing (eg nerve) cello Delta binds to Notch on surrounding cells and signals themto not become the same type of cell as the

Delta‐expressing cell1048707 Both Delta and Notch are single‐pass transmembrane proteins and both requireproteolytic processing to functionbull While it is not clear what function proteolytic cleavage of Delta plays it is clear

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

mediated by the presence of cell‐surface signal protein calledDelta on the developing (eg nerve) cello Delta binds to Notch on surrounding cells and signals themto not become the same type of cell as the

Delta‐expressing cell1048707 Both Delta and Notch are single‐pass transmembrane proteins and both requireproteolytic processing to functionbull While it is not clear what function proteolytic cleavage of Delta plays it is clear

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

Delta‐expressing cell1048707 Both Delta and Notch are single‐pass transmembrane proteins and both requireproteolytic processing to functionbull While it is not clear what function proteolytic cleavage of Delta plays it is clear

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

that proteolysis of Notch is essential to its signaling functionso Binding of Delta to Notch induces proteolytic cleavage of Notch in two places

1)Cleavage of extracellular domain near the membrane releases the

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

extracellular binding domain 2)More

importantly cleavage of the cytoplasmic tail of Notch near the plasma membrane releases the Notch tail that then binds to a gene regulatoryprotein called CSL

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

Binding of the Notch tail to CSL converts CSL from a transcriptional repressor to a transcriptional activator1048707 The main genes that are activated by Notch signaling code for gene regulatory proteins that block

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

expression of genes required by the cell tofollow the same developmental as the Delta-expressing cell

2 Wnt PATHWAY ‐ another regulated PROTEOLYSIS pathway

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

Wnt proteins bind to frizzled receptors and inhibit the degradation of

β‐catenin

bull Wnt proteins act as local mediators to control many aspects of animal development

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

bull The Frizzled family of cell surface receptors are seven‐pass transmembrane proteins that bind and respond to Wnt proteins

o Frizzled receptors resemble G‐protein‐linked receptors in structure and some but

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

not most can signal through G‐proteins and inositol phospholipidsbull Frizzled receptors primarily signal through pathways involving acytosolic protein called Dishevelledo Dishevelled acts by regulating the

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

proteolysis of a multifunctional protein called β‐cateninbull Most β‐catenin found in cells is associated with cadherins which are transmembrane adhesion proteins

Any β‐catenin not associated with cadherins is rapidly

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

degraded by proteolysis involving a large degradation complex which binds β‐catenin and contains 3 other proteins

Glycogen synthase kinase‐3β (GSK‐3β) is a SerThr kinase that phosphorylates β‐catenin thus marking it for ubiquitylation

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

and rapid degradation by proteasomes

Adenomatous polyposis coli (APC) is a tumor suppressor protein named for involvement in a type of benign tumor (adenoma) in the colon which initially forms as a polyp that can eventually become

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

malignant APC promotes degradation of β‐catenin by increasing the affinity of the degradation complex for β‐catenin which then promotes its phosphorylation by GSK‐3βbull Mutations in the APC protein occur in 80 of colon cancers

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

These mutations inhibit APCrsquos ability to bind β‐catenin so that β‐catenin accumulates in the nucleus stimulating transcription of c‐Myc leading to uncontrolled cell proliferation and tumor development

Axin is a scaffold protein that holds the

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

degradation complex together

Steps in the activation of the β‐catenin pathway by Wnt

bull Wnt binds to the Frizzled receptor along with a co‐receptor which

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

is related to the low density lipoprotein (LDL) receptor and is calledLDL‐receptor related protein (LRP)bull This binding activates cytosolic Dishevelled protein by an unknownset of events

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

bull Activated Dishevelled then inactivates GSK‐3β by an unknownmechanism that appears to involve casein kinase 1o Inactivation of GSK‐3β means that cytosolic β‐catenin does not get

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

phosphorylated and degradedbull The unphosphorylated β‐catenin accumulates in the nucleus and displaces Groucho (a co‐repressor protein) from the LEF‐1TCF family of gene regulatory proteins thus activating the

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

transcription of Wnt target genes

One of the Wnt target gene is c‐Myc that is a powerful stimulator of cell growth and proliferation

HEDGEHOG

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

Hedgehog proteins act through Patched and Smoothened Receptorsbull The Hedgehog proteins act as local mediators in developmental processes in both vertebrates and invertebrates

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

o The name Hedgehog comes from work in Drosophila where mutation in the Hedgehog genes led to a larva with spiky processes that resemble a Hedgehogo Abnormalities in Hedgehog pathways during development

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

are lethal and in adult cells lead to cancersbull The active form of Hedgehog proteins contains 1)a covalently coupled cholesterol which help to limit its diffusion after it is secreted and 2)a fatty acid chain which is important for signalling activity

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

bull Two transmembrane proteins Patched and Smoothened are cell surface receptors responsible for mediating the effect of Hedgehog on target cellso Patched is 12‐pass transmembrane protein that binds Hedgehog

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

1048707 In the absence of Hedgehog Patched inhibits the activity of Smoothenedo Smoothened is a 7‐pass transmembrane protein that resembles Frizzled receptors1048707 When Hedgehog binds to Patched its inhibition of Smoothened is

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

relieved and Smoothened signals into the cells ultimately activating transcription ofHedgehog target genesbull Cubitus interruptus (Ci) protein is a gene regulatory protein that is proteolytically processed by

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

proteosomes to yield a proteolyzed product of Ci that accumulates in the nucleus where it acts as a transcriptional repressoro In the cytosol unproteolyzed Ci associates with three other proteins such as-

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

1048707 Fused is a SerThr kinase of unknown function1048707 Costal is an anchoring protein that keeps Ci out of the nucleus1048707 Suppressor of Fused is an adaptor protein involved in the activation of gene

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

transcription by Hedgehogbull Hedgehog binds to Patched relieving the inhibition on Smoothened by an unknown mechanismbull Smoothened signals to the Ci‐containing protein complex leading to the inhibition of Ci

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes

proteolysis and releasing of the complex Followed is the release of Intact Ci from the complexbull The intact Ci accumulates in the nucleus and activates transcription of Hedgehog target genes