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Overview: Cellular Messaging
Cell-to-cell communication is essential for bothmulticellular and unicellular organisms
Biologists have discovered some universalmechanisms of cellular regulation
Cells most often communicate with each othervia chemical signals
For example, the fight-or-flight response istriggered by a signaling molecule calledepinephrine
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Cellularcommunication
Types of signaling Contact
Local
Paracrine Synaptic
Long-distance
Endocrinesystem: viahormones
Neuronal: viaelctricity
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Cellularcommunication
Types of signaling Contact
Local
Paracrine Synaptic
Long-distance
Endocrinesystem: viahormones
Neuronal: viaelctricity
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Cellularcommunication
Types of signaling Contact
Local
Paracrine Synaptic
Long-distance
Endocrinesystem: viahormones
Neuronal: viaelctricity
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Cellularcommunication
Types of signaling Contact
Local
Paracrine Synaptic
Long-distance
Endocrinesystem: viahormones
Neuronal: viaelectricity
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Figure 11.1
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Concept 11.1: External signals are convertedto responses within the cell
Concept 11.2: Reception: A signalingmolecule binds to a receptor protein, causingit to change shape
Concept 11.3: Transduction: Cascades of
molecular interactions relay signals fromreceptors to target molecules in thecellConcept
11.4: Response: Cell signaling leads toregulation of transcription or cytoplasmicactivities
Concept 11.5: Apoptosis integrates multiple cell-signalingpathways
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Concept 11.1: External signals areconverted to responses within the cell
Microbes provide a glimpse of the role of cellsignaling in the evolution of life
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Evolution of Cell Signaling
The yeast, Saccharomyces cerevisiae , has twomating types, a and
Cells of different mating types locate each othervia secreted factors specific to each type
A signal transduction pathway is a series ofsteps by which a signal on a cells surface isconverted into a specific cellular response
Signal transduction pathways convert signals ona cells surface into cellular responses
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C o m m u n i c a t i on be tweenm at ing yeas tcel ls
How canthis be
analogizedtopeople?
Exchangeof matingfactors
Receptor factor
a factor Yeast cell,mating type a
Yeast cell,mating type
Mating
New a/ cell
1
2
3
a
a
a/
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How could we find out how long ago cellcommunication evolved?
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How could we find out how long ago cellcommunication evolved?
See if similar mechanisms are present in bacteriaand recently developed organisms like people.
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Individualrod-shapedcells
Spore-formingstructure(fruiting body)
Aggregationin progress
Fruiting bodies
1
2
3
0.5 mm
2.5 mm
The concentration ofsignaling moleculesallows bacteria to senselocal population density
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Local and Long-Distance Signaling
Cells in a multicellular organism communicate bychemical messengers Animal and plant cells have cell junctions that
directly connect the cytoplasm of adjacent cells In local signaling, animal cells may communicate
by direct contact, or cell-cell recognition
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Figure 11.4 Plasma membranes
Gap junctionsbetween animal cells
Plasmodesmatabetween plant cells
(a) Cell junctions
(b) Cell-cell recognition
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Figure 11.5a
Local signaling
Target cell
Secretingcell Secretoryvesicle
Local regulatordiffuses throughextracellular fluid.
(a) Paracrine signaling using local regulators(b) Synaptic signaling withneurotransmitters
Electrical signalalong nerve celltriggers release ofneurotransmitter.
Neurotransmitter
diffuses acrosssynapse.
Target cellis stimulated.
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Figure 11.5b
Long-distance signaling
Endocrine cell Bloodvessel
Hormone travelsin bloodstream.
Target cellspecificallybindshormone.
(c) Endocrine (hormonal) signaling
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The Three Stages of Cell Signaling:
1. Reception2. Transduction
3. Response
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Animation: Overview of Cell SignalingRight- click slide / select Play
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Figure 11.6-1
Plasma membraneEXTRACELLULARFLUID
CYTOPLASM
Reception
Receptor
Signalingmolecule
1
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Figure 11.6-2
Plasma membraneEXTRACELLULARFLUID
CYTOPLASM
Reception Transduction
Receptor
Signalingmolecule
Relay molecules in a signal transductionpathway
2 1
Fig 11 6 3
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Figure 11.6-3
Plasma membraneEXTRACELLULARFLUID
CYTOPLASM
Reception Transduction Response
Receptor
Signalingmolecule
Activationof cellularresponse
Relay molecules in a signal transductionpathway
3 2 1
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Concept 11.2: Reception: A signalingmolecule binds to a receptor protein, causingit to change shape
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Receptors in the Plasma Membrane
There are three main types of membranereceptors
1. G protein-coupled receptors2. Receptor tyrosine kinases3. Ion channel receptors
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G i l d (GPCR ) h l f il f ll
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G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptorsThe G protein acts as an on/off switch: If GDP is bound to the Gprotein, the G protein is inactive
G protein-coupled receptor
Signaling molecule binding site
Segment thatinteracts withG proteins
Figure 11 7b
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Figure 11.7b
G protein-coupledreceptor
2 1
3 4
Plasmamembrane
G protein(inactive)
CYTOPLASM Enzyme
Activatedreceptor
Signalingmolecule
Inactiveenzyme
Activatedenzyme
Cellular response
GDPGTP
GDPGTP
GTP
P i
GDP
GDP
Note: the enzyme is activatedby shape change
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Figure 11.8: The sturcutre of a G Protien-Coupled Receptor
Plasmamembrane
Cholesterol
2-adrenergicreceptors
Moleculeresemblingligand
2 Receptor tyrosine kinase
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2. Receptor tyrosine kinase
Signalingmolecule (ligand)
2 1
3 4
Ligand-binding site
helix in themembrane
Tyrosines
CYTOPLASM Receptor tyrosinekinase proteins
(inactive monomers)
Signalingmolecule
Dimer
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
Tyr
P
P
P
P
P
P
P
P
P
P
P
P
Activated tyrosinekinase regions(unphosphorylateddimer)
Fully activatedreceptor tyrosinekinase(phosphorylated
dimer)
Activated relayproteins
Cellularresponse 1
Cellularresponse 2
Inactiverelay proteins
6 ATP 6 ADP
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Receptor tyrosine kinases (RTKs) aremembrane receptors that attach phosphates totyrosines
Benefit: A receptor tyrosine kinase can triggermultiple signal transduction pathways at once
Tidbit: Abnormal functioning of RTKs is associatedwith many types of cancers
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Figure 11.7d
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g .
Signalingmolecule(ligand)
2 1 3
Gateclosed Ions
Ligand-gatedion channel receptor
Plasmamembrane
Gateopen
Cellularresponse
Gate closed
A ligand-gated ion channel receptor acts as a gate when thereceptor changes shapeWhen a ligand binds to the receptor, the gate allows specific
ions, such as Na+ or Ca
2+, through a channel in the receptor
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Intracellular Receptors
Intracellular receptor proteins are found in thecytosol or nucleus of target cells
Small or hydrophobic chemical messengerscan readily cross the membrane and activatereceptors Examples of hydrophobic messengers are the
steroid and thyroid (lipid soluble) hormones ofanimals
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Figure 11.9-1
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gHormone(testosterone)
Receptorprotein
Plasmamembrane
DNA
NUCLEUS
CYTOPLASM
EXTRACELLULARFLUID
Figure 11.9-2
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gHormone(testosterone)
Receptorprotein
Plasmamembrane
Hormone-receptorcomplex
DNA
NUCLEUS
CYTOPLASM
EXTRACELLULARFLUID
Figure 11.9-3
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Hormone(testosterone)
Receptorprotein
Plasmamembrane
Hormone-receptorcomplex
DNA
NUCLEUS
CYTOPLASM
EXTRACELLULARFLUID
Figure 11.9-4
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Hormone(testosterone)
Receptorprotein
Plasmamembrane
Hormone-receptorcomplex
DNA
mRNA
NUCLEUS
CYTOPLASM
EXTRACELLULARFLUID
Figure 11.9-5
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Hormone(testosterone)
Receptorprotein
Plasmamembrane
EXTRACELLULARFLUID
Hormone-receptorcomplex
DNA
mRNA
NUCLEUS
CYTOPLASM
New protein
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Concept 11.3: Transduction: Cascades ofmolecular interactions relay signals fromreceptors to target molecules in the cell
Signal transduction usually involves multiple steps
What are some benefits of a multistep pathwaya.k.a. cascade?
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Concept 11.3: Transduction: Cascades ofmolecular interactions relay signals fromreceptors to target molecules in the cell
Signal transduction usually involves multiple steps,
a.k.a. cascade? Benefit 1: can amplify a signal: (A few moleculescan produce a large cellular response)
Benefit 2: provide more opportunities for
coordination and regulation of the cellular response
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Protein Phosphorylation andDephosphorylation is the cascades signal
Protein kinases transfer phosphates from ATP toprotein, a process called phosphorylation
Protein phosphatases remove the phosphatesfrom proteins, a process called dephosphorylation This phosphorylation and dephosphorylation
system acts as a molecular switch, turning
activities on and off or up or down, as required
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Figure 11.10
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Receptor
Signaling molecule
Activated relay
molecule
Inactiveprotein kinase
1 Activeproteinkinase
1
Activeproteinkinase
2
Activeproteinkinase
3
Inactiveprotein kinase2
Inactiveprotein kinase
3
Inactiveprotein
Activeprotein
Cellularresponse
ATPADP
ATPADP
ATPADP
PP
PP
PP
P
P
P
P i
P i
Pi
upstream/downstreamregulation
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Small Molecules and Ions as SecondMessengers
The extracellular signal molecule (ligand) thatbinds to the receptor is a pathways firstmessenger
Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout acell by diffusion
Cyclic AMP and calcium ions are common secondmessengers
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Figure 11.11
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Adenylyl cyclase Phosphodiesterase
Pyrophosphate
AMP
H2O
ATP
P i P
cAMP
What other organic molecule docAMP resemble?
Why?
Figure 11.12
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G protein
First messenger(signaling moleculesuch as epinephrine)
G protein-coupled
receptor
Adenylyl
cyclase
Secondmessenger
Cellular responses
Proteinkinase A
GTP
ATPcAMP
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Calcium I ons and I nosi tol Tr iphosphate (I P 3 )
Calcium ions (Ca 2+) act as a second messenger inmany pathways
Calcium is an important second messengerbecause cells can regulate its concentration
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Figure 11.13
l
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Mitochondrion
EXTRACELLULARFLUID
Plasmamembrane
Ca 2 pump
Nucleus
CYTOSOL
Ca 2 pump
Ca 2 pump
Endoplasmicreticulum(ER)
ATP
ATP
Low [Ca2
]High [Ca2
]Key
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Animation: Signal Transduction PathwaysRight- click slide / select Play
Figure 11.14-1: Calcium and IP 3 in signaling pathways
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G protein
EXTRA-CELLULARFLUID
Signaling molecule(first messenger)
G protein-coupledreceptor Phospholipase C
DAG
PIP 2
IP 3(second messenger)
IP 3-gatedcalcium channel
Endoplasmicreticulum (ER)
CYTOSOL
Ca 2
GTP
Figure 11.14-2
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G protein
EXTRA-CELLULARFLUID
Signaling molecule(first messenger)
G protein-coupledreceptor Phospholipase C
DAG
PIP 2
IP 3(second messenger)
IP 3-gatedcalcium channel
Endoplasmicreticulum (ER)
CYTOSOL
Ca 2 (second
messenger)
Ca 2
GTP
Figure 11.14-3
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G protein
EXTRA-CELLULARFLUID
Signaling molecule(first messenger)
G protein-coupledreceptor Phospholipase C
DAG
PIP 2
IP 3(second messenger)
IP 3-gatedcalcium channel
Endoplasmicreticulum (ER)
CYTOSOL
Variousproteinsactivated
Cellularresponses
Ca 2 (second
messenger)
Ca 2
GTP
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Concept 11.4: Response: Cell signaling leads toregulation of transcription or cytoplasmicactivities
The final activated molecule in the signalingpathway may have a response in the cytoplasm(e.g. changing shape of cytoskeleton or regulatingenzymes) or function as a transcription factor
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Figure 11.15Growth factor Reception
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ReceptorReception
Transduction
CYTOPLASM
Response
Inactivetranscriptionfactor
Activetranscriptionfactor
DNA
NUCLEUS mRNA
Gene
Phosphorylationcascade
P
Reception
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Cytoplasmicresponse to asignal:the stimulationof glycogen
breakdown byepinephrine.
Reception
Transduction
Response
Binding of epinephrine to G protein-coupled receptor (1 molecule)
Inactive G protein
Active G protein (10 2 molecules)
Inactive adenylyl cyclaseActive adenylyl cyclase (10 2)
ATP
Cyclic AMP (104)
Inactive protein kinase AActive protein kinase A (10 4)
Inactive phosphorylase kinaseActive phosphorylase kinase (10 5)
Inactive glycogen phosphorylaseActive glycogen phosphorylase (10 6)
GlycogenGlucose 1-phosphate
(10 8 molecules)
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Signaling pathways can also affect theoverall behavior of a cell, for example,changes in cell shape
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RESULTS
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Wild type yeast (with shmoos) Fus3 formin
Matingfactoractivatesreceptor.
Matingfactor G protein-coupled
receptor
Shmoo projectionforming
Formin
G protein binds GTPand becomes activated.
2
1
3
4
5
P
P
P
PForminFormin
Fus3
Fus3Fus3
GDP GTPPhosphory-
lationcascade
Microfilament
Actinsubunit
Phosphorylation cascadeactivates Fus3, which movesto plasma membrane.
Fus3 phos-phorylatesformin,activating it.
Formin initiates growth ofmicrofilaments that formthe shmoo projections.
CONCLUSION
What is this showing?
Figure 11.17a
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Wild type (with shmoos)
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Fine-Tuning of the Response
There are four aspects of fine-tuning to consider:1. Amplification of the signal (and thus the
response)2. Specificity of the response3. Overall efficiency of response, enhanced by
scaffolding proteins4. Termination of the signal
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Signal Amplif ication
Enzyme cascades amplify the cells response At each step, the number of activated products is
much greater than in the preceding step
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Figure 11.18 The specificity of cell signaling.
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Signaling
molecule
Receptor
Relaymolecules
Response 1
Cell A. Pathway leadsto a single response.
Response 2 Response 3 Response 4 Response 5
Activationor inhibition
Cell B. Pathway branches,leading to two responses.
Cell C. Cross-talk occursbetween two pathways.
Cell D. Different receptorleads to a differentresponse.
Figure 11.19
Signaling Efficiency: Scaffolding Proteins
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Signalingmolecule
Receptor
Plasmamembrane
Scaffoldingprotein
Threedifferentprotein
kinases
g g y: gand Signaling Complexes
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Termination of the Signal
Inactivation mechanisms are an essential aspectof cell signaling If ligand concentration falls, fewer receptors will be
bound Unbound receptors revert to an inactive state
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Concept 11.5: Apoptosis integrates multiplecell-signaling pathways
Apoptosis is programmed or controlled cellsuicide
WHY IS THIS FUNCTION CRITICAL?
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Concept 11.5: Apoptosis integrates multiplecell-signaling pathways
Apoptosis is programmed or controlled cellsuicide
Components of the cell are chopped up andpackaged into vesicles that are digested byscavenger cells
Apoptosis prevents enzymes from leaking out of a
dying cell and damaging neighboring cells
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Figure 11.20: white blood cell apoptosis
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2 m
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Apoptosis in the Soil Worm Caenorhabditiselegans
Apoptosis is important in shaping an organismduring embryonic development
The role of apoptosis in embryonic developmentwas studied in Caenorhabditis elegans
In C. elegans , apoptosis results when proteins thataccelerate apoptosis override those that put the
brakes on apoptosis
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Figure 11.21
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Mitochondrion
Ced-9
protein (active)inhib i t s Ced-4activity
Receptorfor death-signaling
molecule
Ced-4 Ced-3
Inactive proteins
(a) No death signal
Death-signalingmolecule
Ced-9(inactive)
Cellformsblebs
ActiveCed-4
ActiveCed-3
Otherproteases
NucleasesActivationcascade
(b) Death signal
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Apoptotic Pathways and the Signals ThatTrigger Them
Caspases are the main proteases ( what arethese? ) that carry out apoptosis
Apoptosis can be triggered by An extracellular death-signaling ligand DNA damage in the nucleus Protein misfolding in the endoplasmic reticulum
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Apoptosis may be involved in some diseases (forexample, Parkinsons and Alzheimers);interference with apoptosis may contribute tosome cancers
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Figure 11.22: apoptosis in paw development of the mouse
Interdigital tissueCells undergoing
apoptosisSpace between
digits1 mm
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REVIEW
Reception1 2 3 Transduction Response
Receptor
Signaling
molecule
Relay molecules
Activation
of cellularresponse