Cell Signalling Pathways

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Cell Signalling Biology Michael J. Berridge r Module 2 r Cell Signalling Pathways 2 r1

Module 2

Cell Signalling Pathways

Synopsis

Cells use a large number of clearly defined signalling pathways to regulate their activity. In this module,attention is focused on the On mechanisms responsible for transmitting information into the cell. Thesesignalling pathways fall into two main groups depending on how they are activated. Most of them areactivated by external stimuli and function to transfer information from the cell surface to internal effectorsystems. However, some of the signalling systems respond to information generated from within thecell, usually in the form of metabolic messengers. For all of these signalling pathways, information isconveyed either through protein--protein interactions or it is transmitted by diffusible elements usuallyreferred to as second messengers. Cells often employ a number of these signalling pathways, and

cross-talk between them is an important feature. In this section, attention is focused on the propertiesof the major intracellular signalling pathways operating in cells to regulate their cellular activity.

During the processes of development, specific cell types select out those signalling systems that aresuitable to control their particular functions. One of the aims of this website is to understand how theseunique cell-specific signalsomes function to regulate different mammalian cell types.

Intracellular signalling pathwaysThere are a large number of intracellular signalling path-ways responsible for transmitting information within thecell. They fall into two main categories. The majority re-spond to external stimuli arriving at the cell surface, usu-

ally in the form of a chemical signal (neurotransmitter,hormone or growth factor), which is received by recept-ors at the cell periphery that function as molecular an-tennae embedded in the plasma membrane. These recept-ors then transfer information across the membrane usinga variety of transducers and amplifiers that engage a di-verse repertoire of intracellular signalling pathways (Path-ways 1--16 in Module 2: Figure cell signalling pathways).The phosphoinositide signalling and Ca2 + signalling sys-tems (Pathways 2--6) have been grouped together becausethey contain a number of related signalling pathways thatoften interact with each other. The other categories arethe pathways that are activated by signals generated fromwithin the cell (Pathways 17 and 18). There are a number ofmetabolic messengers that act from within the cell to initi-ate a variety of signalling pathways. GTP-binding proteinsoften play a central role in the transduction process re-sponsible for initiating many of these signalling pathways.

All of these signalling pathways generate an internalmessenger that is responsible for relaying information tothe sensors that then engage the effectors that activate cel-lular responses. The main features of the signalling path-ways summarized in Module 2: Figure cell signalling path-ways are outlined below:

Green text indicates links to content within this module; blue textindicates links to content in other modules.

Please cite as Berridge, M.J. (2012) Cell Signalling Biology;doi:10.1042/csb0001002

1. Cyclic AMP signalling pathway. One of the first sig-nalling systems to be characterized was the cyclicAMPsignalling pathway, which ledto the secondmes-senger concept that applies to many other signallingsystems. The idea is that the external stimulus arriving

at the cell surface is the first messenger, which is thentransformed at the cell surface by adenylyl cyclase(AC) into a second messenger, cyclic AMP, which ispart of the signalling cascade that then activates down-stream effectors.

2. Cyclic ADP-ribose (cADPR) signalling and nicotinicacidadenine dinucleotide phosphate (NAADP) sig-nalling systems function in Ca2 + signalling. An ADP--ribosyl cyclase (ADP-RC) is responsible for generat-ing these two second messengers.

3. Voltage-operated channels (VOCs) contribute toCa2 + signalsbycontrollingtheentryofexternalCa2 +

in excitable cells.4. Receptor-operated channels (ROCs) contribute to

Ca2 + signals by controlling Ca2 + entry in both excit-able and non-excitable cells.

5. Stimuli that activate phospholipase C (PLC) to hy-drolyse PtdIns4,5P2 (also known as PIP2) generate anumber of signalling pathways: Inositol 1,4,5-trisphosphate (InsP3)/Ca2 + sig-

nalling cassette Diacylglycerol (DAG)/protein kinase C (PKC) sig-

nalling cassette PtdIns4,5P2 signalling cassette Multipurpose inositol polyphosphate signalling

pathway6. PtdIns 3-kinase signalling is activated by stimuli

that stimulate PtdIns 3-kinase to phosphorylate PIP2

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to form the lipid second messenger PtdIns3,4,5P3(PIP3).

7. Nitric oxide (NO)/cyclic GMP signalling pathway.Nitric oxide (NO) synthase (NOS) generates the gasNO that acts both through cyclic GMP and nitrosyla-tion reactions. NO has a particularly important rolein modulating the activity of other pathways such as

Ca2 + signalling.8. Redox signalling. Many receptors act through

NADPH oxidase (NOX) to form reactive oxygenspecies, such as the superoxide radical (O2 ) andhydrogen peroxide (H2O2), which act to regulate theactivity of specific signalling proteins such as tyrosinephosphatases, transcription factors and ion channels.The O2 participates in the nitrosylation reaction inPathway 7.

9. Mitogen-activated protein kinase (MAPK) signalling.This is a classical example of a protein phosphoryla-tion cascade that often begins with Ras and consists of

a number of parallel pathways that function to controlmany cellular processes and particularly those relatedto cell proliferation, cell stress and apoptosis.

10. Nuclear factor B (NF-B) signalling pathway. Thissignalling system has a multitude of functions. It isparticularly important in initiating inflammatory re-sponses in macrophages and neutrophils as part of aninnate immune response to invading pathogens.

11. Phospholipase D (PLD) signalling pathway. This is alipid-based signalling system that depends upon thehydrolysis of phosphatidylcholine by phospholipaseD (PLD) to give phosphatidic acid (PA), which func-tions as a second messenger to control a variety of

cellular processes.12. Sphingomyelin signalling pathway. Certain growth

factors and cytokines hydrolyse sphingomyelin togenerate two second messengers that appear to haveopposing effects in the cell. Ceramide seems to pro-mote apoptosis, whereas sphingosine 1-phosphate(S1P) stimulates cell proliferation. S1P may also re-lease Ca2 + from internal stores. The action of S1P iscomplicated in that it is released from the cell, whereit can act as a hormone to stimulate external receptors.

13. Janus kinase (JAK)/signal transducer and activator oftranscription (STAT) signalling pathway.Thisisafast-

track signal transduction pathway for transferring in-formation from cell-surface receptors into the nucleus.The Janus kinases (JAKs) are tyrosine kinases thatphosphorylate the signal transducers and activatorsof transcription (STATs), which carry the informationinto the nucleus.

14. Smad signalling pathway. This pathway mediates theaction of the transforming growth factor (TGF-)superfamily, which controls transcription through theSmad transcription factors.

15. Wnt signalling pathways. These pathways play an im-portant role in both development and cell prolifera-tion.

16. Hedgehog signalling pathway. This pathway re-sembles the Wnt signalling pathway in that it alsofunctions to regulate development and cell prolifer-

ation. The ligand Hedgehog (Hh) acts through thetranscription factor GLI.

17. Hippo signalling pathway. This pathway has a coreprotein kinase cascade that has some similarities to theMAPkinase cascade in that a seriesof serine/threonineprotein kinases function to regulate the transcriptionof a number of genes that function in cell growth,

proliferation and apoptosis.18. Notch signalling pathway. This is a highly conserved

signalling system that functions in developmental pro-cesses related to cell-fate determination particularly instem cells. The notch receptor generates the transcrip-tion factor NICD (Notch intracellular domain).

19. Endoplasmic reticulum (ER) stress signalling. The en-doplasmic reticulum (ER) stress signalling pathwayconcerns the mechanisms used by the ER to transmitinformation to the nucleus about the state of proteinprocessing within the lumen of the ER.

20. AMP signalling pathway. This pathway is regulated

by adenosine monophosphate (AMP), which func-tions as a metabolicmessenger to activate an importantpathway for the control of cell proliferation.

Not included in Module 2: Figure cell signalling path-ways are some additional signalling pathways that havespecific functions in regulating various aspects of cell meta-bolism, such as sterol sensing and cholesterol biosynthesis,that control the level of cholesterol in cell membranes. An-other example is found in the NAD signalling pathways,where NAD + functions to regulate a number of cellularprocesses, including energy metabolism, gene transcrip-tion, DNA repair and perhaps ageing as well.

These cassettes then engage a variety of effectors thatare responsible for activating cellular responses. All ofthese mechanisms (Module 1: Figure signal transmissionmechanisms) depend upon information transfer mechan-isms whereby information is transferred along an orderlysequence of events to activate the internal effectors re-sponsible for inducing a great variety of cellular responses.

Cyclic AMP signalling pathwayCyclic AMP is a ubiquitous second messenger thatregulates a multitude of cellular responses. Cyclic

AMP formation usually depends upon the activation ofG-protein-coupled receptors (GPCRs) that use heterotri-meric G proteins to activate the amplifier adenylyl cyc-lase (AC), which is a large family of isoforms that dif-fer considerably in both their cellular distribution andthe way they are activated. There are a number of cyclicAMP signalling effectors such as protein kinase A (PKA),the exchange proteins activated by cyclic AMP (EPACs)that activate the small GTP-binding protein Rap1 and thecyclic nucleotide-gated channels (CNGCs). These variouseffectors are then responsible for carrying out the cyclicAMP signalling functions that include control of metabol-ism, gene transcription and ion channel activity. In many

cases, these functions are modulatory in that cyclic AMPoften acts to adjust the activity of other signalling path-ways and thus has a central role to play in the cross-talk

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Module 2: Figure cell signalling pathways

Wnt b-catenin

Hh GLI

MST1/2 Lats1/2 YAP

Notch NICD

Ras Erk1/2

SmadTGF-

NOX O H O+2 22

JAK STAT

SESNOPSER

RALULL

EC

PI 3-K PIP

PLD PA

p38

NF-kBIkBs

JNK

Smase ceramide/ S1P

PLC

DAG

PIP2

VOC

ROC

ADP-RC

Ca2+

3

AC cAMP

NAADP

IP3

cADPR

Metabolism AMP AMPK

NOS NONitrosylation

cGMP

T

PECER

SRECUDSNART&SRO

ILUMITS

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

19

20

18

ATF6, PERK

SCAP, bHLH

ER

TCEFFE

SRO

SROSNES

Summary of the major signalling pathways used by cells to regulate cellular processes.

Cells havea numberof signalling systems that are capable of responding eitherto external stimuli or to internal stimuli. In thecase of theformer, externalstimuli acting on cell-surface receptors are coupled to transducers to relay information into the cell using a number of different signalling pathways(Pathways 1--17). Internal stimuli derived from the endoplasmic reticulum (ER) or from metabolism activate signalling pathways independently ofexternal signals (Pathways 18 and 19). All of these pathways generate an internal messenger that then acts through an internal sensor to stimulatethe effectors that bring about different cellular responses. As described in the text, the names of these signalling pathways usually reflect a majorcomponent(s) of the pathway.

between signalling pathways. This modulatory function isparticularly evident in the case of Ca2 + signalling in bothneuronal and muscle cells. Many of the functions of cyclicAMP depend upon the precise location of PKA relative

to both its upstream and downstream effectors. A familyofA-kinase-anchoring proteins (AKAPs) determines thiscellular localization of PKA as well as a number of othersignalling components. The OFF reactions responsible forremoving cyclic AMP are carried out by either cyclic AMPhydrolysis or by cyclic AMP efflux from the cell.

Cyclic AMP formationThe formation of cyclic AMP can be activated by avery large number of cell stimuli, mainly neurotrans-mitters and hormones (Module 1: Figure stimuli forcyclic AMP signalling). All these stimuli are detec-

ted by G-protein-coupled receptors (GPCRs) that useheterotrimeric G proteins, which are the transducers thatare responsible for either activating or inhibiting the en-

zyme adenylyl cyclase (AC) (Module 2: Figure heterotri-meric G protein signalling). In the case of AC stimulation,the external stimulus binds to the GPCR that functionsas a guanine nucleotide exchange factor (GEF) to replace

GDP with GTP, which dissociates the heterotrimeric com-plex into their G and G subunits (Module 2: Figurecyclic AMP signalling). The GSGTP complex activatesAC,whereas GiGTPinhibitsAC.TheGsubunits haveGTPase activity that hydrolyses GTP to GDP, thus ter-minating their effects on AC. The endogenous GTPase ofGSGTP is inhibited by cholera toxin and this causes thepersistent activation of the intestinal fluid secretion thatresults in the symptoms ofcholera.

Adenylyl cyclase (AC)The adenylyl cyclase (AC) family is composed of ten iso-

forms: nine of them are membrane-bound (AC1--AC9),while one of them is soluble (AC10) (Module 2: Tableadenylyl cyclases). The domain structure of AC1--AC9 is

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Module 2: Figure adenylyl cyclase structure

TM 1-6 TM 7-12

C1

C1

C1

N N

N N

NH NH

N N

N N

O O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O O

O

O

O

O

O

P

P

P

P

P

P

OHOH OH

C

H HH H

C

2 2

C2

C2

AC 1 - 9

AC 10

ATP

Pyrophosphate

Plasma membrane

Cyclic AMP

1 72 83 94 105 116 12

C2

Domain structure of adenylyl cyclase (AC).

The nine membrane-bound adenylyl cyclases (AC1--AC9) have a similar domain structure. The single polypeptide has a tandem repeat of sixtransmembrane domains (TM) with TM1--TM6 in one repeat and TM7--TM12 in the other. Each TM cassette is followed by large cytoplasmic domains(C1 and C2), which contain t he catalytic regions that convert ATP into cyclic AMP. As shown in the lower panel, the C1 and C2 domains come togetherto form a heterodimer. TheATP-binding site is locatedat the interface betweenthese two domains. Thesoluble AC10isoform lacks the transmembraneregions, but it retains the C1 and C2 domains that are responsible for catalysis.

characterized by having two regions where there are sixtransmembrane regions (Module 2: Figure adenylyl cy-clase structure). The large cytoplasmic domains C1 andC2, which contain the catalytic region, form a heterodimerand co-operate with each other to convert ATP into cyclicAMP.

Cyclic AMP signalling effectorsCyclic AMP is a highly versatile intracellular messen-ger capable of activating a number of different effectors(Module 2: Figure cyclic AMP signalling). An example ofsuch effectors is the exchange proteins activated by cyc-lic AMP (EPACs), which act to stimulate Rap. Anothergroup of effectors are the cyclic nucleotide-gated channels(CNGCs) (Module3: FigureCa2 + entry mechanisms)thatplay a particularly important role in the sensory systemsresponsibleforsmellandtaste.Mostof theactions of cyclicAMP are carried out by protein kinase A (PKA).

Protein kinase A (PKA)Many of the actions of cyclic AMP are carried out by pro-tein kinase A (PKA), which phosphorylates specific siteson downstream effector processes (Module 2: Figure cyc-lic AMP signalling). PKA is composed of two regulatory(R) subunits and two catalytic (C) subunits. The way in

which cyclic AMP activates PKA is to bind to the R sub-units, which then enables the C subunits to phosphorylatea wide range of different substrates [Module 2: Figure pro-

tein kinase A (PKA)]. Of the two types of PKA, proteinkinase A (PKA) I is found mainly free in the cytoplasmand has a high affinity for cyclic AMP, whereas proteinkinase A (PKA) II has a much more precise location by be-ing coupled to the A-kinase-anchoring proteins (AKAPs).The AKAPs are examples of the scaffolding proteins thatfunction in the spatial organization of signalling pathwaysby bringing PKA into contact with its many substrates.The scaffolding function of the AKAPs is carried out byvarious domains such as the conserved PKA-anchoringdomain [yellow region in Module 2: Figure protein kinaseA (PKA)], which is a hydrophobic surface that binds toan extended hydrophobic surface on the N-terminal di-

merization region ofthe R subunits. At the other end ofthe molecule, there are unique targeting domains (blue)that determine the way AKAPs identify and bind specificcellular targets in discrete regions of the cell.

Protein kinase A (PKA) IType I protein kinase A (PKA) associates with the RI iso-forms. As for all isoforms, the R subunits form dimersthrough their N-terminal dimerization/docking domains[yellow bar in Module 2: Figure protein kinase A (PKA)].In addition to holding two R subunits together, this N-terminal region is also responsible for docking to the A-

kinase-anchoring proteins (AKAPs), as occurs for PKAII. However, the RI isoforms have a very low affinity forthe AKAPs and are thus mainly soluble. Cyclic AMP acts

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Module 2: Table adenylyl cyclasesRegulatory properties and distribution of adenylyl cyclase.

Adenylyl cyclase(AC) isoform G G Gi or Go

Modulation by Ca2 + , calmodulin(CaM), Ca2 + /CaM kinase II(CaMKII), protein kinase C (PKC),protein kinase A (PKA) Tissue distribution

AC1 Go CaM and PKC CaMKII Brain, adrenal medullaAC2 -- PKC Brain, skeletal and cardiac muscle, lungAC3 CaM and PKC CaMKII Brain, olfactory epithelium

AC4 PKC Brain, heart, kidney, liverAC5 Ca2 + and PKC PKA Brain, heart, kidney, liver, lung, adrenal

AC6 PKC Ca2 + and PKA UbiquitousAC7 PKC Ubiquitous, high in brainAC8 CaM Brain, lung, heart, adrenalAC9 Brain, skeletal muscleAC10 -- -- -- Activated by HCO3

Testis

The membrane-bound adenylyl cyclases (AC1--AC9) are widely distributed. They are particularly rich in brain, but are also expressed inmany other cell types. The soluble AC10 is restricted to the testis. The primary regulation of the AC1--AC9 isoforms is exerted throughcomponents of the heterotrimeric G proteins, which are dissociated upon activation of neurotransmitter and hormonal receptors into theirand subunits. They are all activated by Gs, but only some of the isoforms are inhibited by Gi. The G subunit is able to activatesome isoforms, but inhibits others. The isoforms also differ in the way they are modulated by components of other signalling pathwayssuch as Ca2 + and PKC. Some of the others are inhibited by PKA, which thus sets up a negative-feedback loop whereby cyclic AMP caninhibit its own production. Modified from Table I in Whorton and Sunahara 2003. Reproduced from Handbook of Cell Signaling, Volume 2(edited by R.A. Bradshaw and E.A. Dennis), Whorton, M.R. and Sunahara, R.K., Adenylyl cyclases, pp. 419--426. Copyright (2003), withpermission from Elsevier.

by binding to the tandem cyclic AMP-binding domains torelease active C subunits that then phosphorylate specificsubstrates. Since theRI subunits have a highercyclicAMP-binding affinity, PKA I will be able to respond to the lowercyclic AMP concentrations found globally within the bulkcytoplasm.

Protein kinase A (PKA) IIA characteristic feature of Type II protein kinase A (PKA)is that the regulatory dimer is made up of RII sub-units. Since this RII subunit has a much higher affin-ity for the A-kinase-anchoring proteins (AKAPs), PKAII is usually docked to this scaffolding protein and thushas a much more precise localization to specific cellulartargets.

The substrates phosphorylated by cyclic AMP (Module2: Figure cyclic AMP signalling) fall into two main groups:the cyclic AMP substrates that regulate specific cellularprocesses and the cyclic AMP substrates that are compon-ents of other signalling systems.

Cyclic AMP substrates that regulate specific cellularprocesses:

In neurons, cyclic AMP acts through PKA to phos-phorylate Ser-845 on the AMPA receptor (Module 3:Figure AMPA receptor phosphorylation).

Cyclic AMP acting through PKA stimulates thefructose-2,6-bisphosphatase component to lower thelevel of fructose 2,6-bisphosphate, which reduces glyco-lysis and promotes gluconeogenesis (Module 2: FigureAMPK control of metabolism).

In insulin-secreting -cells, the salt-inducible kinase 2(SIK2) that phosphorylates transducer of regulated cyc-lic AMP response element-binding protein (TORC)is inhibited by a cyclic AMP/PKA-dependent phos-

phorylation (Module 7: Figure -cell signalling). PKA phosphorylates the hormone-sensitive lipase

(HLS) that initiates the hydrolysis of triacylglycerol

to free fatty acids and glycerol in both white fat cells(Module 7: Figure lipolysis and lipogenesis) and inbrown fat cells (Module 7: Figure brown fat cell).

PKA phosphorylates the phosphorylase kinase thatconverts inactive phosphorylase b into active phos-phorylase a in skeletal muscle (Module 7: Figure skeletalmuscle E-C coupling) and in liver cells (Module 7: Fig-ure glycogenolysis and gluconeogenesis).

PKA activates the transcription factor cyclic AMP re-sponse element-binding protein (CREB) (Module 4:

Figure CREB activation). This activation is a criticalevent in the induction of gluconeogenesis in liver cells(Module 7: Figure liver cell signalling).

PKA inhibits the salt-inducible kinase 2 (SIK2) that nor-mally acts to phosphorylate TORC2, thereby prevent-ing it from entering the nucleus to facilitate the activityof CREB (Module 7: Figure liver cell signalling).

PKA phosphorylates inhibitor 1 (I1), which assists theprotein phosphorylation process by inactivating proteinphosphatase 1 (PP1) .

PKA contributes to the translocation and fusion of ves-icles with the apical membrane during the onset of acid

secretion by parietal cells (Module 7: Figure HCl secre-tion). PKA phosphorylates the regulatory (R) domain on the

cystic fibrosis transmembrane conductance regulator(CFTR) to enable it to function as an anion channel(Module 3: Figure CFTR channel).

In the small intestine, PKA phosphorylates the cysticfibrosis transmembrane conductance regulator (CFTR)channel (Module 3: Figure CFTR channel) that is re-sponsible for activating fluid secretion (Module 7: Fig-ure intestinal secretion). Uncontrolled activation ofcyclic AMP formation by cholera toxin results incholera.

In kidney collecting ducts, cyclic AMP acts throughPKA to phosphorylate Ser-256 on the C-terminal cyto-plasmic tail ofaquaporin 2 (AQP2), enabling this water

http://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_AMPA_receptor_phosphorylationhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_AMPA_receptor_phosphorylationhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_AMPA_receptor_phosphorylationhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_AMPA_receptor_phosphorylationhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Insulin_secretingb_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Insulin_secretingb_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Insulin_secretingb_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Insulin_secretingb_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#White_fat_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_lipolysis_and_lipogenesishttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_lipolysis_and_lipogenesishttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Brown_fat_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_brown_fat_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_brown_fat_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_skeletal_muscle_EC_couplinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_skeletal_muscle_EC_couplinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_skeletal_muscle_EC_couplinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_skeletal_muscle_EC_couplinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_glycogenolysis_and_glyconeogenesishttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_glycogenolysis_and_glyconeogenesishttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_glycogenolysis_and_glyconeogenesishttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_glycogenolysis_and_glyconeogenesishttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_glycogenolysis_and_glyconeogenesishttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#CREBhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#CREBhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Protein_phosphatase1_PP1http://www.cellsignallingbiology.org/csb/005/csb005.pdf#Protein_phosphatase1_PP1http://www.cellsignallingbiology.org/csb/005/csb005.pdf#Protein_phosphatase1_PP1http://www.cellsignallingbiology.org/csb/005/csb005.pdf#Protein_phosphatase1_PP1http://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_HCl_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_HCl_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_HCl_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_HCl_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_HCl_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_HCl_secretionhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Cystic_fibrosis_TM_conduct_regul_CFTRhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Cystic_fibrosis_TM_conduct_regul_CFTRhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Cystic_fibrosis_TM_conduct_regul_CFTRhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CFTR_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CFTR_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CFTR_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Cystic_fibrosis_TM_conduct_regul_CFTRhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Cystic_fibrosis_TM_conduct_regul_CFTRhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Cystic_fibrosis_TM_conduct_regul_CFTRhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CFTR_channelhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_intestinal_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_intestinal_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_intestinal_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_intestinal_secretionhttp://www.cellsignallingbiology.org/csb/012/csb012.pdf#Cholerahttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Collecting_ducthttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Collecting_ducthttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Aquaporinshttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Aquaporinshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Collecting_ducthttp://www.cellsignallingbiology.org/csb/012/csb012.pdf#Cholerahttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_intestinal_secretionhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CFTR_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Cystic_fibrosis_TM_conduct_regul_CFTRhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CFTR_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Cystic_fibrosis_TM_conduct_regul_CFTRhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_HCl_secretionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Parietal_cellhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Protein_phosphatase1_PP1http://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#CREBhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_glycogenolysis_and_glyconeogenesishttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_skeletal_muscle_EC_couplinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_brown_fat_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Brown_fat_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_lipolysis_and_lipogenesishttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#White_fat_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Insulin_secretingb_cellshttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_AMPA_receptor_phosphorylation


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Module 2: Figure cyclic AMP signalling

S

S i

i

CyclicAMP

PKA

GTP

GDP

Choleratoxin

GDP

GTP

5AMP

CyclicGMP

5GMP

P

PP

P

PP

P

P

P

P

P

Rap1

EPAC

DAG

CREB

Phosphorylasekinase

Lipase

Ca2+

Ca2++

+

+

+

+ + + ++

+++

+

--

+

Soluble adenylyl cyclase PDE

cGMP PDE

AMPAR

CFTR

PLNER/SR

SERCA

RYR

Ca 1.1

Ca 1.2

V

V

3HCO

F-2,6-Pphosphatase

2

CNGC

Adenylylcyclase

Stimulatory agonists Inhibitory agonists

InsP3

PLC

ABCC4

Organization and function of the cyclic AMP signalling pathway.

Cyclic AMP is formed both by membrane-bound adenylyl cyclase and by the bicarbonate-sensitive soluble adenylyl cyclase. The former is regulatedby both stimulatory agonists that act through the S subunit or through inhibitory agonists that act through either the i or the subunits. Theincrease in cyclic AMP then acts through three different effector systems. It acts through the exchange protein activated by cyclic AMP (EPAC), whichfunctions to activate Rap1. It can open cyclic nucleotide-gated channels (CNGCs). The main action of cyclic AMP is to activate protein kinase A (PKA)to phosphorylate a large number of downstream targets. Some of these drive specific processes such as gene transcription through phosphorylationof cyclic AMP response element-binding protein (CREB), and activation of ion channels [e.g. AMPA receptors and cystic fibrosis transmembraneconductance regulator (CFTR)] and various enzymes that control metabolism [e.g. fructose 2,6-bisphosphate (F-2,6-P 2) 2-phosphatase, lipase andphosphorylase kinase]. Other downstream targets are components of other signalling pathways such as the cyclic GMP phosphodiesterase (cGMPPDE), the phospholamban (PLN) that controls the sarco/endo-plasmic reticulum Ca2 + -ATPase (SERCA), the ryanodine receptor (RYR) and the Ca2 +

channels CaV1.1 and CaV1.2.

channel to fuse with the apical membrane to allow wa-ter to enter the cell (Module 7: Figure collecting ductfunction).

In blood platelets, cyclic AMP activates thephosphorylation of vasodilator-stimulated phos-phoprotein (VASP), which is a member of theEna/vasodilator-stimulated phosphoprotein (VASP)family resulting in a decrease in the actin-dependentprocesses associated with clotting (Module 11: Figureplatelet activation).

Cyclic AMP substrates that are components of othersignalling systems:

Phosphorylation of the cyclic GMP phosphodiesterasePDE1A by PKA results in a decrease in its sensitivityto Ca2 + activation.

Entry of Ca2 + through the L-type CaV1.1 channel(Module 3: Figure CaV1.1 L-type channel) and the L-type CaV1.2 channel (Module 3: Figure CaV1.2 L-typechannel) is enhanced through PKA-dependent phos-phorylation.

PKA-dependent phosphorylation of dopamine- andcyclic AMP-regulated phosphoprotein of apparent mo-

lecular mass 32 kDa(DARPP-32) functionsas a molecu-lar switch to regulate the activity of protein phosphatase1 (PP1).

The ryanodine receptor 2 (RYR2) is modulatedby phos-phorylation through PKA, which is associated with thecytoplasmic head through an AKAP (Module 3: Figureryanodine receptor structure).

Sarco/endo-plasmic reticulum Ca2 + -ATPase 2a(SERCA2a) increases its Ca2 + -pumping activity whenthe inhibitory effect of phospholamban (PLN) isremoved following its phosphorylation by PKA onSer-16 (Module 5: Figure phospholamban mode ofaction).

Salt-inducible kinase 2 (SIK2)The salt-inducible kinase 2 (SIK2) functions to phos-phorylate the transducer of regulated CREB (TORC2),thereby preventing it from entering the nucleus to facil-itate the activity of the transcriptional factor cyclic AMPresponse element-bindingprotein (CREB) (Module4:Fig-ure CREB activation). It functions to regulate TORC2in liver cells (Module 7: Figure liver cell signalling) andin insulin-secreting -cells (Module 7: Figure -cell sig-nalling).

Exchange proteins activated by cyclicAMP (EPACs)Other targets for the second messenger cyclic AMP are theexchangeproteinsactivatedbycAMP(EPACs).Oneofthe

http://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_collecting_duct_functionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_collecting_duct_functionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_collecting_duct_functionhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_collecting_duct_functionhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ena_VASP_familyhttp://www.cellsignallingbiology.org/csb/011/csb011.pdf#Fig11_platelet_activationhttp://www.cellsignallingbiology.org/csb/011/csb011.pdf#Fig11_platelet_activationhttp://www.cellsignallingbiology.org/csb/011/csb011.pdf#Fig11_platelet_activationhttp://www.cellsignallingbiology.org/csb/011/csb011.pdf#Fig11_platelet_activationhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#PDE1Ahttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#CaV1_1_Ltype_channelshttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#CaV1_1_Ltype_channelshttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#CaV1_1_Ltype_channelshttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_1_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_1_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_1_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#DARPP_32http://www.cellsignallingbiology.org/csb/005/csb005.pdf#DARPP_32http://www.cellsignallingbiology.org/csb/005/csb005.pdf#DARPP_32http://www.cellsignallingbiology.org/csb/005/csb005.pdf#DARPP_32http://www.cellsignallingbiology.org/csb/005/csb005.pdf#DARPP_32http://www.cellsignallingbiology.org/csb/003/csb003.pdf#Ryanodine_receptors_RYRshttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_ryanodine_receptor_structurehttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_ryanodine_receptor_structurehttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_ryanodine_receptor_structurehttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_ryanodine_receptor_structurehttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Phospholambanhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Fig5_phospholamban_mode_of_actionhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Fig5_phospholamban_mode_of_actionhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Fig5_phospholamban_mode_of_actionhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Fig5_phospholamban_mode_of_actionhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#CREBhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#CREBhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Liver_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_bCell_signallinghttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Insulin_secretingb_cellshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_liver_cell_signallinglhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Liver_cellhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Fig4_CREB_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#CREBhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Fig5_phospholamban_mode_of_actionhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Phospholambanhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#Sarco_endoplasmic_reticulum_ATPase_SERCAhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_ryanodine_receptor_structurehttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Ryanodine_receptors_RYRshttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#DARPP_32http://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_2_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV1_1_Ltype_channelhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#CaV1_1_Ltype_channelshttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#PDE1Ahttp://www.cellsignallingbiology.org/csb/011/csb011.pdf#Fig11_platelet_activationhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ena_VASP_familyhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_collecting_duct_function


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Module 2: Figure protein kinase A (PKA)

C

C

CTandem

cyclicAMP-bindingdomains

RI

PKA I PKA II

RI

RI RI

RIIRII

RIIRII

C

C

C

C

P

P P

Cyclic AMP

Substrate SubstrateSubstrate

Substrate

Substrate

Substrate

Cyclic AMP

AKAP

A

KAP

Cellular target

Cellular target

The functional organization of protein kinase A (PKA).

There are two types of PKA, type I PKA (PKA I) and type II PKA (PKA II), which differ primarily in the type of R subunits that associate with the Csubunits. There are four R subunit isoforms (RI, RI, RIIand RII), which have somewhat different properties with regard to their affinity for cyclic

AMP and their ability t o a ssociate with the A-kinase-anchoring proteins (AKAPs). It is these different R subunits that define the properties of the twotypes of PKA.

functions of EPACs is to activate Rap1 and Rap2B, whichhave many functions, many of which are related to con-trolling actin dynamics. In addition, the EPAC/Rap path-way can activate phospholipase C (PLC) and this mech-anism has been implicated in the control of autophagy(Module 11: Figure autophagy signalling mechanisms).

Cyclic AMP signalling functionsThe cyclic AMP signalling pathway functions in the con-trol of a wide range of cellular processes:

Cyclic AMP suppresses spontaneous Ca2 + oscillationsduring oocyte maturation.

Cyclic AMP has a potent anti-inflammatory action by

inhibiting the activity of macrophages (Module 11: Fig-ure macrophage signalling) and mast cells (Module 11:Figure mast cell inhibitory signalling).

Melanocortin 4 receptors (MC4Rs) on second-orderneurons use the cyclic AMP signalling pathwayto induce the hypothalamic transcription factorSingle-minded 1 (Sim1) to decrease food intake andweight loss (Module 7: Figure control of food intake).

Cyclic AMP mediates the action of lipolytic hormonesin white fat cells by stimulating a hormone-sensitivelipase (Module 7: Figure lipolysis and lipogenesis).

Heat production by brown fat cells is controlled bynoradrenaline acting through cyclic AMP (Module 7:

Figure brown fat cell). The phosphorylation of dopamine- and cyclic

AMP-regulated phosphoprotein of apparent molecu-

lar mass 32 kDa (DARPP-32) co-ordinates the activ-ity of the dopamine and glutamate signalling pathwaysin medium spiny neurons (Module 10: Figure mediumspiny neuron signalling).

Adrenaline-induced glycogenolysis in skeletal musclecells depends upon a cyclic AMP-dependent phos-phorylation of phosphorylase kinase (Module 7: Figureskeletal muscle E-C coupling).

Activation of the cyclic AMP-dependent transcriptionfactor cyclic AMP response element-binding protein(CREB) contributes to the regulation of glucagon bio-synthesis in glucagon-secreting -cells (Module 7: Fig-ure -cell signalling).

Cyclic AMP hydrolysisThere are two OFF reactions of the cyclic AMP sig-nalling pathway, cyclic AMP efflux from the cell and cyclicAMP hydrolysis. The latter is carried out by a family ofphosphodiesterase enzymes that hydrolyse cyclic AMP toAMP (Module 2: Figure cyclic AMP signalling).

Cyclic AMP effluxThere are two OFF reactions for the cyclic AMP sig-nalling pathway, cyclic AMP hydrolysis and cyclic AMPefflux from the cell (Module 2: Figure cyclic AMP sig-

nalling). The latter is carried out by ABCC4, which is oneof the ATP-binding cassette (ABC) transporters (Module3: Table ABC transporters).

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Module 2: Figure G protein binary switching

GDP

Gprotein

Gprotein

GTP

GDP

Ion channel modulation

GTP

Cyclic AMP signalling

3InsP /DAG signalling

Phosphate

Signalling responsesGEFs

Input from cell surface receptors

Cytoskeletal remodelling

Redox signalling

PtdIns 3-kinase signalling

MAP kinase signalling

PLD signalling

GAPs

GTPase-activatingfactors

Guanine nucleotide

exchange factors

Signal transduction through G protein binary switching.

All GTP-binding proteins (G proteins) function through a binary switching mechanism that is driven by the binding of GTP. The G protein is inactivewhen bound to GDP. When this GDP is exchanged for GTP, the G protein is activated and can stimulate a number of different signalling responses.The rapid switching to the active state is facilitated by the guanine nucleotide exchange factors (GEFs) that receive the information coming in fromthe receptors on the cell surface. By contrast, the GTPase-activating proteins (GAPs) accelerate the OFF reaction by enhancing the hydrolysis of GTPto GDP.

GTP-binding proteins

There are a large number of GTP-binding proteins, whichusually are referred to as G proteins, which play a cent-ral role in cell signalling as molecular switches (Module2: Figure G protein binary switching). These G proteinsare also GTPases, and the switching is driven by both thebinding of GTP and its hydrolysis to GDP. The G proteinis inactive when bound to GDP, but when the GDP is ex-changed forGTP, theG protein/GTP complex is activeandtransfers information down the signalling pathway untilthe endogenous GTPase activity hydrolyses GTP to GDP.The G proteins belong to two groups, the heterotrimericG proteins and the monomeric G proteins, which have

separate, but overlapping, functions.

Heterotrimeric G proteinsThe heterotrimeric G proteins function as transducers forthe G-protein-coupled receptors (GPCRs) that activate anumber of cell signalling pathways (Module 1: Table G-protein coupled receptors). These G proteins are made upfrom 16 G, five G and 11 G genes (Module 2: Tableheterotrimeric G proteins). These different subunits arecharacterized by having various lipid modifications thatserve to insert them into the plasma membrane, where theyare positioned to detect information coming in from theGPCRs and to relay it to various amplifiers. The Gsub-

units are either palmitoylated or myristoylated near the N-terminus, whereas the G subunits are prenylated. Theheterotrimeric G proteins are extremely versatile signalling

elements, and both the Gsubunit and the G subunit

are able to relay information to downstream components(Module 2: Figure heterotrimeric G protein signalling).

These heterotrimeric G proteins exist in two states.When the G subunit is bound to GDP, it forms a com-plex with G subunits to form the inactive heterotri-meric complex. When the GPCRs, which are sensitive to awide range of stimuli (Module 1: Figure stimuli for cyclicAMP signalling), are activated, they function as a guan-ine nucleotide exchange factor (GEF) to replace the GDPwith GTP. The binding of GTP not only activates theG subunit, but also liberates the G subunit, both ofwhich can activate a range of signalling systems. This signal

transduction process is switched off when the endogen-ous GTPase activity of the G subunit hydrolyses GTPto GDP and the G/GDP complex recombines with theG subunit to reform the inactive heterotrimeric com-plex. The normal rate of GTPase activity is very low (fourto eight conversions per s), which means that the two sub-units have a long time to find their targets. However, thereare two mechanisms for speeding up the GTPase activity.Firstly, some of the targets can act to accelerate the GT-Pase activity. Secondly, a family ofregulators of G proteinsignalling (RGS) proteins function as GTPase-activatingproteins (GAPs) that accelerate the G subunit GTPaseactivity more than 1000-fold.

There are G-protein receptor kinases (GRKs) such as-adrenergic receptor kinase 1 (ARK1), which phos-phorylate active receptors to provide binding sites for

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Module 2: Table heterotrimeric G proteinsThe heterotrimeric proteins are assembled from subunits taken from the G protein (G), G protein (G) and G protein (G) families.

Heterot rimeric G protein Funct ion

G protein (G) subunitsGs Stimulate adenylyl cyclase

Golf Stimulate adenylyl cyclaseGi1 Inhibit adenylyl cyclaseGi2 Inhibit adenylyl cyclaseGi3 Inhibit adenylyl cyclase

Go1 Inhibit adenylyl cyclaseGo2 Inhibit adenylyl cyclaseGt1 Stimulate cyclic GMP phosphodiesterase in rod photoreceptorsGt2 Stimulate cyclic GMP phosphodiesterase in rod photoreceptorsGz Close K + channels. Inhibits exocytosis (see Module 10: Figure lactotroph regulation)

Ggust Stimulate phospholipase C (PLC) (see Module 10: Figure taste receptor cells and Module 7:Figure L cells)

Gq Stimulate phospholipase C (PLC)G11 Stimulate phospholipase C (PLC)G14 Stimulate phospholipase C (PLC)G15 Stimulate phospholipase C (PLC)G16 Stimulate phospholipase C (PLC)G12 Stimulate RhoGEFs to activate Rho (Module 2: Figure Rho signalling)G13 Stimulate RhoGEFs to activate Rho (Module 2: Figure Rho signalling)

G protein (G) subunits; 1--5 These subunits combine with subunits to form dimers that have a number of control functions(for details see Module 2: Figure heterotrimeric G protein signalling)

G protein (G) subunits; 1--11 These subunits combine with subunits to form dimers that have a number of control functions(for details see Module 2: Figure heterotrimeric G protein signalling)

arrestin that prevent the heterotrimeric proteins frombinding the receptor and this leads to receptor desensit-ization (Module 1: Figure homologous desensitization).

The active G/GTP and G subunits are able to re-lay information to a large number of signalling pathways,which are described in more detail for the different sig-nalling pathways:

The cyclic AMP signalling pathway (Module 2: Figurecyclic AMP signalling). The activation of phospholipase C (PLC) in the

inositol 1,4,5-trisphosphate (InsP3)/Ca2 + signallingcassette (Module 2: Figure PLC structure and function).

Modulation of the CaV2family of N-type andP/Q-typechannels (Module 3: Figure CaV2 channel family).

Activation of the PtdIns 3-kinase signalling pathway(Module 2: Figure PtdIns 3-kinase signalling).

Activation ofphosphodiesterase 6 (PDE6) during pho-totransduction in photoreceptors (Module 10: Figurephototransduction).

Golf functions in sperm motility and chemotaxis. Ggust, which is also known as gustudin, functions in

taste cells and in the L cells that detect food componentsin the lumen of the intestine L cells (Module 7: FigureL cells).

Regulators of G protein signalling (RGS)The regulators of G protein signalling (RGS) are a largefamily of approximately 30 proteins that function asGTPase-activating proteins (GAPs) for the heterotrimericGproteins(Module 2: Figure heterotrimeric G protein sig-nalling). The Gsubunit has a low intrinsic GTPase activ-ity and this is greatly increased by the RGS proteins. RGSstructure is defined by an RGS-box region that is respons-

ible for binding to G/GTP. However, many of the RGSproteins contain a number of other protein--protein inter-action domains, such as PDZ, phosphotyrosine-binding

(PTB), pleckstrin homology (PH) and phox homology(PX) domains, indicating that, in addition to their GAPactivity, they mayhave other functions. Oneof these mightbe the regulation of the G-protein-activated inwardly rec-tifying K + (GIRK) channel.

The function of RGS proteins has been clearly definedin phototransduction, where RGS9 acts to accelerate GTPhydrolysis by Gt (step 6 in Module 10: Figure photo-

transduction).

Monomeric G proteinsThe monomeric GTP-binding proteins (G proteins) be-long to a large family of approximately 150 members. Raswas the founding member, and the family is often referredtoasthe Ras family of small G proteins. Within this family,it is possible to recognize five subfamilies: Ras, Rho, Rab,Ran and ADP-ribosylation factor (Arf) (Module 2: Tablemonomeric G protein toolkit). The Ran family plays a rolein nuclear transport, whereas the large Rab family func-tions in membrane trafficking. The Ras and Rho family are

primarilyinvolved in cell signalling, where they function asbinary switches to control a number of cell signalling sys-tems. This binary switch is driven by the binding of GTP,which represents the ON reaction, and is followed by thehydrolysis of the GTP by the endogenous GTPase activ-ity. Most attention has focused on a small number of thesesignal transducers, and the following will be described indetail to illustrate their role in cell signalling:

Arf signalling mechanisms Cdc42 signalling mechanisms Rab signalling mechanisms Rac signalling mechanisms Ras signalling mechanisms Rap signalling mechanisms Rho signalling mechanisms

http://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10lactotroph_regulationhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10lactotroph_regulationhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Arrestinshttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Receptor_desensitizationhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Receptor_desensitizationhttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Receptor_desensitizationhttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Fig1_homologous_desensitizationhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Modulation_CaV2_family_N_PQ_R_type_channhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Modulation_CaV2_family_N_PQ_R_type_channhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Modulation_CaV2_family_N_PQ_R_type_channhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Modulation_CaV2_family_N_PQ_R_type_channhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Modulation_CaV2_family_N_PQ_R_type_channhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV2_channel_familyhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#PDE6http://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/008/csb008.pdf#Sperm_motility_and_chemotaxishttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#L_cellshttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PDZ_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PDZ_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PX_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PX_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PX_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PX_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PX_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PX_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PX_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#G_protein_activated_inwardly_rectifyinghttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#G_protein_activated_inwardly_rectifyinghttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#G_protein_activated_inwardly_rectifyinghttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#G_protein_activated_inwardly_rectifyinghttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#G_protein_activated_inwardly_rectifyinghttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#G_protein_activated_inwardly_rectifyinghttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#G_protein_activated_inwardly_rectifyinghttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PX_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PH_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PTB_domainhttp://www.cellsignallingbiology.org/csb/006/csb006.pdf#PDZ_domainhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#L_cellshttp://www.cellsignallingbiology.org/csb/008/csb008.pdf#Sperm_motility_and_chemotaxishttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10phototransductionhttp://www.cellsignallingbiology.org/csb/005/csb005.pdf#PDE6http://www.cellsignallingbiology.org/csb/003/csb003.pdf#Fig3_CaV2_channel_familyhttp://www.cellsignallingbiology.org/csb/003/csb003.pdf#Modulation_CaV2_family_N_PQ_R_type_channhttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Fig1_homologous_desensitizationhttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Receptor_desensitizationhttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Arrestinshttp://www.cellsignallingbiology.org/csb/007/csb007.pdf#Fig7_L_cellhttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10taste_receptor_cellshttp://www.cellsignallingbiology.org/csb/010/csb010.pdf#Fig10lactotroph_regulation


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Module 2: Figure heterotrimeric G protein signalling

Cyclic AMP

Cyclic AMP

Cyclic AMP

InsP Ca

InsP Ca

Cyclic GMP

DAG

+

Cytoskeleton

Cytoskeleton

Cytoskeleton

DAG

GIRK

Ca 1.2V

AC

AC

AC

3

3

2+

2+

2+

GDP

GDPGTP

GRK

Arrestins

s

i

q

12/13

t

GTP

PI 3-K

Ca

V

PIP3

PLC

G protein

Rho A

Cdc42

Rac

PDE6

PLC

GPCR

Stimulus

G responses

G responses

RGSproteins

P

Heterotrimeric G proteins function as transducers to activate many signalling pathways.

External stimuli thatbind to G protein-coupled receptors (GPCRs) act as guanine nucleotide exchange factors (GEFs) for theheterotrimeric G proteins.When the GDP on the Gsubunit is replaced with GTP, the complex dissociates into G/GTP and G subunits that are then capable of activatingor inhibiting a wide range of signalling systems. Most of the actions are stimulatory, but some are inhibitory, as illustrated by the yellow arrows. Theregulators of G protein signalling (RGS) proteins function as GTPase-activating proteins (GAPs) to facilitate the GTPase activity of the G subunit,which is the OFF reaction that terminates signalling. G protein receptor kinase (GRK) phosphorylates active receptors and provides binding sites forarrestin that result in receptor desensitization by preventing the heterotrimeric G proteins from binding the receptor.

Ras signalling mechanismsRas is a small (21 kDa) GTPase that plays a central roleas a signal transducer for a number of signalling sys-tems. It was first identified as a transducer for the tyr-osine kinase-linked receptors (Module 1: Figure stimulifor enzyme-linked receptors), where it functions to re-lay information to the mitogen-activated protein kinase(MAPK) signalling pathway. It is now known that ac-tivated Ras is able to relay information to a number ofother signalling pathways. Like other G proteins (Module2: Figure G protein binary switching), Ras functions asa binary switch that is activated by binding GTP. There

are thus two critical aspects to Ras action: how is theswitch controlled and how is information relayed out todifferent signalling pathways (Module 2: Figure Ras sig-nalling)? With regard to the first question, the ON reac-tion of the binary switch is controlled by a number of Rasguanine nucleotide exchange factors (RasGEFs) such asSon-of-sevenless (SoS), Ras guanine nucleotide release-in-ducing factors (RasGRFs) and Ras guanine nucleotidereleasing proteins (RasGRPs) (Module 2: Table mono-meric G protein toolkit). This conversion of RasGDP intoRasGTP is inhibited by the tumour suppressor proteinmerlin. Neurofibromatosis type 2 is caused by mutationsin merlin.

There are a number of Ras GTPase-activating proteins(RasGAPs) that accelerate the OFF reaction by speed-ing up the hydrolysis of GTP to GDP by Ras. Examples

of such RasGAPs include p120 RasGAP, neurofibromin,SynGAP, Ca2 + -promoted Ras inactivator (CAPRI) andRas GTPase-activating-like (RASAL). The function ofsome of these RasGAPs such as CAPRI and RASAL areattracting considerable attention because they are Ca2 + -sensitive proteins that rapidly translocate to the mem-brane through their C2 domains whenever there is an in-crease in the level of Ca2 + . SynGAP, which is expressedmainly in brain, is also activated by Ca2 + following itsphosphorylation by Ca2 + /calmodulin-dependent proteinkinase II (CaMKII). The role of Ca2 + in modulating theactivity of both the RasGEFs and RasGAPs indicates an

important feedback interaction between the Ca2 +

and Rassignalling pathways.The Ras signalling mechanism relays information to a

number of signalling targets:

It activates Raf to initiate the MAPK signalling pathway(Module 2: Figure ERK signalling).

It activates phospholipase C (PLC) (Module 2: FigurePLC structure and function).

It activates the PtdIns 3-kinase signalling pathway. Ras can activate a family of RalGEFs such as Ral-

GDP dissociation stimulator that then activates the Ralproteins (RalA and RalB) (Module 2: Figure Ras sig-

nalling). One of the functions of RalA is to stimulate thephospholipase D signalling pathway (Module 2: FigurePLD signalling).

http://www.cellsignallingbiology.org/csb/001/csb001.pdf#Fig1_stimuli_for_enzyme_linked_receptorshttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Fig1_stimuli_for_enzyme_linked_receptorshttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Fig1_stimuli_for_enzyme_linked_receptorshttp://www.cellsignallingbiology.org/csb/001/csb001.pdf#Fig1_stimuli_for_enzyme_linked_receptorshttp://www.cellsignallingbiology.org/csb/012/csb012.pdf#Merlinhttp://www.cellsignallingbiology.org/csb/012/csb012.pdf#Merlinhttp://www.cellsignallingbiology.org/csb/012/csb012.pdf#Neurofibromatosis_type_2http://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/004/csb004.pdf#Ca_calmodulin_depend_prot_kinase_IIhttp://www.cellsignallingbiology.org/csb/012/csb012.pdf#Neurofibromatosis_type_2http://www.cellsignallingbiology.org/csb/012/csb012.pdf#Merlinhttp://www.cellsignallingbiology.org/csb/001

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