cell signaling 2007 cells sense and send information (signals) cells communicate with each other...
TRANSCRIPT
Cell Signaling
2007
• Cells sense and send information (signals)• Cells communicate with each other• Cells must sense and respond to changes in
the environment
The signal can come from inside the cell, from another cell, or from the environment.
©2004 Lee Bardwell
Cell Signaling
Generic Signaling Pathway
Signal
Receptor (sensor)
Transduction Cascade
OutputSomething
happens
outside
inside (cytosol)
©2002 Lee Bardwell
Something
happens
Responses to cell signaling
• Gene expression is altered at the level of transcription, RNA processing or translation
• Enzyme activities are altered• Protein-protein interactions are induced or
inhibited• The localization of certain proteins and other
stuff is altered
biochemically
©2002 Lee Bardwell
Something
happens
Responses to cell signaling
The Cell…– divides or stops dividing– differentiates– commits suicide or kills something– moves somewhere or stops moving– alters its metabolism– passes on the signal
Physiologically
©2002 Lee Bardwell
What can be a signal?- almost anything
• Peptides - insulin, glucagon...• Proteins• Amino acid derivatives - epinephrine, histamine• Other small biomolecules - ATP• Steroids, prostaglandins• Gases - Nitric Oxide (NO)• Photons• Damaged DNA• Odorants, tastants
©2002 Lee Bardwell
Steroid Hormone Signaling Pathway
Signal
(steroid)
Receptor (txn factor)
Steroid Hormone Signaling Pathway
Output
∆ gene expression
∆ cell physiology
Signaling cascades have many steps
Past:Enumeratecomponents
Now:• Modules• Circuits/ Design Logic• Cross-talk• Specificity
Adrenaline signaling
• Signal: Adrenaline (epinephrine)– Secreted by adrenal gland
• Receptor: -adrenergic receptor
• Response:– Breakdown of glycogen to glucose to
provide energy for “fight-or-flight”
Insulin signaling
• Signal: insulin– Secreted by cells of pancreas
• Receptor: a receptor kinase• Response:
– Sugar is taken up from bloodstream into cells
• Diabetes - type 1, type 2
Growth factor signaling
The growth of multicellular organisms is regulated by more than just nutrient availability
NUTRIENTS
NUTRIENTSunicellulareukaryote
multicellulareukaryote
a edigner
Cells in multicellular eukaryotes require permission signals from growth factors
NUTRIENTS
NUTRIENTS
a edigner
Disregulation of growth factor signal transduction leads to cancer
NUTRIENTS
cellulartransformation
NUTRIENTS
Some growth factors
• EGF - epidermal growth factor
• FGF - fibroblast growth factor
• NGF - nerve growth factor
• PDGF - platelet-derived growth factor
• Insulin-like GF
All of these bind to a class of receptors known as “Receptor Kinases”
Receptors with enzymatic activity
Protein kinases and phosphatases
- Add/remove phosphates to/from proteins
- Involved in all signaling from cell surface recetors, and in most other signaling too
©2002 Lee Bardwell
Protein Kinase Reaction
Kinase
Substrate
P P PPATP
P P P
Protein Kinase ReactionPhosphorylation of protein substrates
Product
Phosphorylation can flip a protein from “active” to “inactive” or vis-versa
ATP
ADP
RAF
MEK
MAPKMAPK
TXY TXY
MEKPP
PP
P P
SP TP SP TP
The Mitogen-Activated Protein Kinase (MAPK) Cascade
Neoplastic phenotype
Ras
MEKK
MEK/MAPKK
MAPKs
Raf
receptor
growth factor
MEK1
ERK1 ERK2
MEK2
Elk1/SRF
HER2
Fos Jun
FOS
CCND1
cyclin D1
How do protein kinases
recognize their protein
substrates ?
Specificity in MAPK Signalling
Protein Kinase Reaction
Kinase
Substrate
P P PPATP
P P P
Protein Kinase ReactionPhosphorylation of protein substrates
Product
Active site - target peptide interaction is not enough for
specificity
Kinase
Substrate
Tethering function:Tethering function: Grewal et al (2006) Cell. Grewal et al (2006) Cell. Signal. 18:123Signal. 18:123
Bardwell Lab
• Lee Bardwell• Jane Bardwell• Kandarp Shah• Lamar
Blackwell• Tom Whisenant• Jeff Rogers• Pascal Krotee