Cell CommunicationCell Communication

Evolution of Cell SignalingEvolution of Cell Signaling• A signal-transduction pathway is a series of A signal-transduction pathway is a series of

steps by which a signal on a cell’s surface is steps by which a signal on a cell’s surface is converted into a specific cellular responseconverted into a specific cellular response

• Signal transduction pathways convert signals on Signal transduction pathways convert signals on a cell’s surface into cellular responsesa cell’s surface into cellular responses

• Pathway similarities suggest that ancestral Pathway similarities suggest that ancestral signaling molecules evolved in prokaryotes and signaling molecules evolved in prokaryotes and have since been adopted by eukaryoteshave since been adopted by eukaryotes

  Communication Between Mating Yeast CellsCommunication Between Mating Yeast Cells

factorReceptor

Exchange of mating factors. Each cell type secretes a mating factor that binds to receptors on the other cell type.

Mating. Binding of the factors to     receptors induces changes in the cells that lead to their fusion.

New a/ cell. The nucleus of the fused cell includes all the genes from the a and cells.

factorYeast cell,

mating type aYeast cell,

mating type

a/

a

a

1

3

2

Cells CommunicationCells Communication

• Direct contactDirect contact• Paracrine signalingParacrine signaling• Endocrine signalingEndocrine signaling• Synaptic signalingSynaptic signaling

Direct ContactDirect Contact• Cells touch each other and signal molecules travel through Cells touch each other and signal molecules travel through

special connections called communicating junctionsspecial connections called communicating junctions• Communicating junctions link the cytoplasms of 2 cells together, Communicating junctions link the cytoplasms of 2 cells together,

permitting the controlled passage of small molecules or ions permitting the controlled passage of small molecules or ions between them. between them.

Plasma membranes

Gap junctionsbetween animal cells

Cell junctions

Cell-cell recognition

Plasmodesmatabetween plant cells

(a) Paracrine signaling. A secreting cell acts on nearby target cells by discharging molecules of a local regulator (a growth factor, for example) into the extracellular fluid.

(b) Synaptic signaling. A nerve cell releases neurotransmitter molecules into a synapse, stimulating the target cell.

Hormone travelsin bloodstreamto target cells

(c) Hormonal signaling. Specialized endocrine cells secrete hormones into body fluids, often the blood. Hormones may reach virtually all body cells.

Local regulator diffuses through extracellular fluid

Secretingcell

Target cell

Secretoryvesicle

Electrical signalalong nerve celltriggers release ofneurotransmitter

Neurotransmitter diffuses across

synapse

Target cellis stimulated

Local signaling Long-distance signaling

Endocrine cellBloodvessel

Targetcell

Cell Communication In AnimalsCell Communication In Animals• In many other cases, animal cells communicate using local In many other cases, animal cells communicate using local

regulators, messenger molecules that travel only short distancesregulators, messenger molecules that travel only short distances• In long-distance signaling, plants and animals use chemicals called In long-distance signaling, plants and animals use chemicals called

hormoneshormones

Cell SignalingCell Signaling

EXTRACELLULARFLUID

Receptor

Signal molecule

Relay molecules in a signal transduction pathway

Plasma membraneCYTOPLASM

Activationof cellularresponse

Reception Transduction Response1 2 3

• The cells of a organism communicate with each other by releasing The cells of a organism communicate with each other by releasing signal moleculessignal molecules that bind to that bind to receptor proteinsreceptor proteins located either on or inside of located either on or inside of target cellstarget cells..

• Three stages of cell signaling:Three stages of cell signaling:• Reception - each target cell has receptors that detect a specific signal molecule and binds to Reception - each target cell has receptors that detect a specific signal molecule and binds to

itit

• Transduction – binding of the signal molecule changes the receptor protein in some way that Transduction – binding of the signal molecule changes the receptor protein in some way that initiates transduction or conversion of the signal to a form that can bring about a specific initiates transduction or conversion of the signal to a form that can bring about a specific cellular responsecellular response

• Response – transduced signal triggers a specific cellular response, any cell activityResponse – transduced signal triggers a specific cellular response, any cell activity

ReceptionReception• A signal molecule binds to a receptor protein, A signal molecule binds to a receptor protein,

causing it to change shapecausing it to change shape• The binding between signal molecule (ligand) The binding between signal molecule (ligand)

and receptor is highly specificand receptor is highly specific• A conformational change in a receptorA conformational change in a receptor

• Is often the initial transduction of the signalIs often the initial transduction of the signal

ReceptorsReceptors• Intracellular receptors Intracellular receptors

• Some signal molecules that are small or hydrophobic can pass through Some signal molecules that are small or hydrophobic can pass through the plasma membrane and bind to receptors located inside the cell the plasma membrane and bind to receptors located inside the cell

• Intracellular receptors are cytoplasmic or nuclear proteinsIntracellular receptors are cytoplasmic or nuclear proteins

• Cell surface receptors. - Signal molecules that cannot pass through Cell surface receptors. - Signal molecules that cannot pass through the plasma membrane bind to receptors located on the surface of the plasma membrane bind to receptors located on the surface of the membrane the membrane

Intracellular Receptors Intracellular Receptors

• Gene RegulatorsGene Regulators• Signal molecule joins to the receptor, the receptor Signal molecule joins to the receptor, the receptor

changes shape and a DNA binding site is exposed.changes shape and a DNA binding site is exposed.• The DNA binding site joins to a specific segment of The DNA binding site joins to a specific segment of

DNA and activates (or suppresses) a particular geneDNA and activates (or suppresses) a particular gene

• Enzyme ReceptorEnzyme Receptor• These receptors function as enzymes – proteins that These receptors function as enzymes – proteins that

catalyze (speed up) specific chemical reactions. catalyze (speed up) specific chemical reactions. • When a signal molecule joins to the receptor, the When a signal molecule joins to the receptor, the

receptor’s catalytic domain is activated (or receptor’s catalytic domain is activated (or deactivated).deactivated).

Hormone(testosterone)

EXTRACELLULARFLUID

Receptorprotein

Plasmamembrane

Hormone-receptorcomplex

DNA

mRNA

NUCLEUS

CYTOPLASM

New protein

The steroid hormone testosterone passes through the plasma membrane.

1

Testosterone bindsto a receptor proteinin the cytoplasm,activating it.

2

The hormone-receptor complexenters the nucleusand binds to specific genes.

3

The bound proteinstimulates thetranscription ofthe gene into mRNA.

4

The mRNA istranslated into aspecific protein.

5

  Steroid hormone interacting with an intracellular receptorSteroid hormone interacting with an intracellular receptor

Surface ReceptorsSurface Receptors• Receptors located on the surface of the membrane, 4 types:Receptors located on the surface of the membrane, 4 types:

• Chemically gated ion channelsChemically gated ion channels• Enzymatic receptorsEnzymatic receptors• G-protein-linked receptorsG-protein-linked receptors• IntegrinsIntegrins

Chemically Gated Ion ChannelsChemically Gated Ion Channels

• An ion channel An ion channel receptor acts as a receptor acts as a gate when the gate when the receptor changes receptor changes shapeshape

• When a signal When a signal molecule binds as molecule binds as a ligand to the a ligand to the receptor, the gate receptor, the gate allows specific allows specific ions, such as Naions, such as Na++ or Caor Ca2+2+, through a , through a channel in the channel in the receptorreceptor

Gate close

Cellularresponse

Gate open

Gate close

Ligand-gatedion channel receptor

Plasma Membrane

Signalmolecule(ligand)

GateClosed Ions

Enzymatic ReceptorsEnzymatic Receptors• Embedded in the plasma membrane, with their catalytic site exposed Embedded in the plasma membrane, with their catalytic site exposed

inside the cell. inside the cell. • Catalytic site activated when the signal molecule joins to the receptor. Catalytic site activated when the signal molecule joins to the receptor. • Function as Function as protein kinasesprotein kinases (enzymes that (enzymes that phosphorylate phosphorylate proteins.)proteins.)

Receptor Tyrosine Kinases

Signalmolecule

Signal-binding site

CYTOPLASM

Tyrosines

Signal molecule Helix in the

Membrane

Tyr

Tyr

Tyr

Tyr

Tyr

TyrTyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

Tyr

DimerReceptor tyrosinekinase proteins(inactive monomers)

P

P

PP

P

PTyr

Tyr

Tyr

Tyr

Tyr

TyrP

P

P

P

P

PCellularresponse 1

Inactiverelay proteins

Activatedrelay proteins

Cellularresponse 2

Activated tyrosine-kinase regions(unphosphorylateddimer)

Fully activated receptortyrosine-kinase(phosphorylateddimer)

6 ATP 6 ADP

G-protein-linked ReceptorsG-protein-linked Receptors• Signal molecule joins to a receptor, the receptor activates a G Signal molecule joins to a receptor, the receptor activates a G

protein protein • The activated G protein can then activate an ion channel or The activated G protein can then activate an ion channel or

enzyme in the plasma membrane.enzyme in the plasma membrane.

G protein

ActivatedG protein

Enzyme orion channel

Activatedenzyme orion channel

G-protein-linked receptor

Signal

Signal-binding site

G-PROTEIN-LINKED RECEPTORS

G-protein-linkedreceptor

Plasma Membrane

EnzymeG-protein(inactive)CYTOPLASM

Cellular response

Activatedenzyme

Activatedreceptor

Signal molecule Inactiveenzyme

Segment thatinteracts withG proteins

GDP

GDP

GTP

GTP

P i

GDP

Second MessengersSecond Messengers• Some enzymatic receptors Some enzymatic receptors

and most G-protein-linked and most G-protein-linked receptors relay their message receptors relay their message into the cell by activating into the cell by activating other molecules or ions other molecules or ions inside the cell.inside the cell.

• These molecules and ions, These molecules and ions, called called second messengerssecond messengers, , transmit the message within transmit the message within the cell. The 2 most common the cell. The 2 most common second messengers are second messengers are cAMP and Ca++cAMP and Ca++

Signal Transduction PathwaysSignal Transduction Pathways• Transduction usually involves multiple stepsTransduction usually involves multiple steps• Multistep pathwaysMultistep pathways

• Can amplify a signalCan amplify a signal• Provide more opportunities for coordination and regulationProvide more opportunities for coordination and regulation

• The molecules that relay a signal from receptor to The molecules that relay a signal from receptor to response are mostly proteinsresponse are mostly proteins

• The receptor activates another protein, which The receptor activates another protein, which activates another, and so on, until the protein activates another, and so on, until the protein producing the response is activatedproducing the response is activated

• At each step, the signal is transduced into a different At each step, the signal is transduced into a different form, usually a conformational changeform, usually a conformational change

  A Phosphorylation CascadeA Phosphorylation Cascade• In many pathways, the signal is transmitted by a cascade of protein In many pathways, the signal is transmitted by a cascade of protein

phosphorylations - phosphatase enzymes remove the phosphatesphosphorylations - phosphatase enzymes remove the phosphates• This phosphorylation and dephosphorylation system acts as a molecular switch, This phosphorylation and dephosphorylation system acts as a molecular switch,

turning activities on and offturning activities on and off

Signal molecule

Activeproteinkinase

1

Activeproteinkinase

2

Activeproteinkinase

3

Inactiveprotein kinase

1

Inactiveprotein kinase

2

Inactiveprotein kinase

3

Inactiveprotein

Activeprotein

Cellularresponse

Receptor

P

P

P 

P

P

P

ATPADP

ADP

ADP

ATP

ATP

PP

PP

PP

Activated relaymolecule

A relay moleculeactivates protein kinase 1.

1

Active protein kinase 1transfers a phosphate from ATPto an inactive molecule ofprotein kinase 2, thus activatingthis second kinase.

2

Active protein kinase 2then catalyzes the phos-phorylation (and activation) ofprotein kinase 3.

3

Finally, active proteinkinase 3 phosphorylates aprotein (pink) that brings about the cell’s response tothe signal.

4

Enzymes called proteinphosphatases (PP)catalyze the removal ofthe phosphate groupsfrom the proteins, making them inactiveand available for reuse.

5

i

i

i

Phosphorylation cascade

cAMP Second MessengercAMP Second MessengerG-protein-signaling pathwayG-protein-signaling pathway

1.1. Signal molecule binds to Signal molecule binds to surface receptorsurface receptor

2.2. Surface receptor Surface receptor activates a G proteinactivates a G protein

3.3. G protein activates the G protein activates the membrane-bound membrane-bound enzyme, adenylyl enzyme, adenylyl cyclasecyclase

4.4. Adenylyl cyclase Adenylyl cyclase catalyzes synthesis of catalyzes synthesis of camp, which binds to a camp, which binds to a target proteintarget protein

5.5. Target protein initiates Target protein initiates cellular changecellular change

First messenger(signal moleculesuch as epinephrine)

ATP

GTP

cAMP

Proteinkinase A

Cellular responses

G-protein-linkedreceptor

Adenylylcyclase

G protein

Second messenger

Cyclic AMPCyclic AMP

O–O O

O

N

O

O

O

O

P P P

P

P P

O

O

O

O

O

OH

CH2

NH2 NH2 NH2

N

N

N

N

N

N

N

N

N

N

NO

O

O

ATP

Ch2CH2

O

OH OH

P

O O

H2O

HOAdenylyl cyclase Phoshodiesterase

Pyrophosphate

Cyclic AMP AMPOH OH

O

i

• Cyclic AMP (cAMP) is one of the most widely Cyclic AMP (cAMP) is one of the most widely used second messengersused second messengers

• Adenylyl cyclase, an enzyme in the plasma Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response membrane, converts ATP to cAMP in response to an extracellular signalto an extracellular signal

Cyclic AMP PathwayCyclic AMP Pathway

Calcium (Ca++) PathwaysCalcium (Ca++) Pathways• Calcium ions (CaCalcium ions (Ca2+2+) act as a second messenger in many pathways) act as a second messenger in many pathways• Calcium is an important second messenger because cells can Calcium is an important second messenger because cells can

regulate its concentrationregulate its concentration

ATP

EXTRACELLULARFLUID

ATPMitochondrion

Ca2+

pump

Plasmamembrane

CYTOSOL

Endoplasmicreticulum (ER)

Ca2+

pump

Ca2+

pump

High [Ca2+]Key

Nucleus

Low [Ca2+]

• A signal transduction pathway may trigger A signal transduction pathway may trigger an increase in calcium in the cytosolan increase in calcium in the cytosol

• Pathways leading to the release of calcium Pathways leading to the release of calcium involve inositol triphosphate (IPinvolve inositol triphosphate (IP33) and ) and

diacylglycerol (DAG) as second diacylglycerol (DAG) as second messengersmessengers

Calcium ions and Inositol Triphosphate (IPCalcium ions and Inositol Triphosphate (IP33))

Ca++ PathwayCa++ Pathway• Signal molecule binds to surface receptorSignal molecule binds to surface receptor• Surface receptor activates a G proteinSurface receptor activates a G protein• G protein activates the membrane-bound G protein activates the membrane-bound

enzyme, phospholipase Cenzyme, phospholipase C• Phospholipase C catalyzes synthesis of Phospholipase C catalyzes synthesis of

inositol triphosphate, which stimulates inositol triphosphate, which stimulates release of Ca++ from ERrelease of Ca++ from ER

• Released Ca++ initiates cellular changeReleased Ca++ initiates cellular change

Calcium and IPCalcium and IP33 in signaling pathways in signaling pathways

2 3

IP3 quickly diffuses throughthe cytosol and binds to an IP3–gated calcium channel in the ERmembrane, causing it to open.

4 The calcium ionsactivate the nextprotein in one or moresignaling pathways.

6 Calcium ions flow out ofthe ER (down their con-centration gradient), raisingthe Ca2+ level in the cytosol.

5

DAG functions asa second messengerin other pathways.

Phospholipase C cleaves aplasma membrane phospholipidcalled PIP2 into DAG and IP3.

EXTRA-CELLULARFLUID

Signal molecule(first messenger)

G protein

G-protein-linkedreceptor

Variousproteinsactivated

Endoplasmicreticulum (ER)

Phospholipase CPIP2

IP3

DAG

Cellularresponses

GTP

Ca2+

(second messenger)

Ca2+

IP3-gatedcalcium channel

A signal molecule bindsto a receptor, leading toactivation of phospholipase C.

1

CYTOSOL

Fine-Tuning of the ResponseFine-Tuning of the Response

• Multistep pathways have two important Multistep pathways have two important benefits:benefits:• Amplifying the signal (and thus the response)Amplifying the signal (and thus the response)• Contributing to the specificity of the responseContributing to the specificity of the response

• Enzyme cascades amplify the cell’s Enzyme cascades amplify the cell’s responseresponse

• At each step, the number of activated At each step, the number of activated products is much greater than in the products is much greater than in the preceding steppreceding step

AmplificationAmplification• Due to the many steps in the cell signaling process, one Due to the many steps in the cell signaling process, one

signal molecule can trigger a “cascade” effectsignal molecule can trigger a “cascade” effect

Cytoplasmic response to a signal: the stimulation of Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrineglycogen breakdown by epinephrine

Glucose-1-phosphate(108 molecules)

Glycogen

Active glycogen phosphorylase (106)

Inactive glycogen phosphorylase

Active phosphorylase kinase (105)

Inactive phosphorylase kinase

Inactive protein kinase A

Active protein kinase A (104)

ATPCyclic AMP (104)

Active adenylyl cyclase (102)

Inactive adenylyl cyclase

Inactive G protein

Active G protein (102 molecules)

Binding of epinephrine to G-protein-linked receptor (1 molecule)

Transduction

Response

Reception

Specificity of Cell SignalingSpecificity of Cell Signaling• Different kinds of cells have Different kinds of cells have

different collections of proteinsdifferent collections of proteins• These differences in proteins These differences in proteins

give each kind of cell give each kind of cell specificity in detecting and specificity in detecting and responding to signalsresponding to signals

• The response of a cell to a The response of a cell to a signal depends on the cell’s signal depends on the cell’s particular collection of proteinsparticular collection of proteins

• Pathway branching and “cross-Pathway branching and “cross-talk” further help the cell talk” further help the cell coordinate incoming signalscoordinate incoming signals

Signalmolecule

Receptor

Relaymolecules

Response 1 Response 2 Response 3

Cell B. Pathway branches,leading to two responses

Cell A. Pathway leads to a single response

Cell C. Cross-talk occursbetween two pathways

Response 4 Response 5

Activationor inhibition

Cell D. Different receptorleads to a different response

Signaling Efficiency: Scaffolding Proteins and Signaling Efficiency: Scaffolding Proteins and Signaling ComplexesSignaling Complexes

• Rather than relying on diffusion of large relay molecules such as proteins, Rather than relying on diffusion of large relay molecules such as proteins, many signal pathways are linked together physically by many signal pathways are linked together physically by scaffolding scaffolding proteins.proteins.

• Scaffolding proteins may themselves be relay proteins to which several Scaffolding proteins may themselves be relay proteins to which several other relay proteins attach.other relay proteins attach.

• This hardwiring enhances the speed, accuracy, and efficiency of signal This hardwiring enhances the speed, accuracy, and efficiency of signal transfer between cells.transfer between cells.

Signalmolecule

Receptor

Scaffoldingprotein

Threedifferentproteinkinases

Plasmamembrane

Figure 11.16