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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 10

Module 2: Figure heterotrimeric G protein signalling

InsP Ca 2+
3 G responses
PLC
Stimulus DAG
q
AC Cyclic AMP
s
AC Cyclic AMP
GPCR i
t PDE6 Cyclic GMP
GRK P
12/13
Rho A Cytoskeleton
Arrestins
GTP
GTP GDP +
Rac Cytoskeleton
GDP
Cdc42 Cytoskeleton
G protein
PI 3-K PIP 3
RGS
proteins GIRK V
2+
Ca 1.2 Ca
V
AC Cyclic AMP
InsP Ca 2+
PLC 3
DAG G responses
Heterotrimeric G proteins function as transducers to activate many signalling pathways.
External stimuli that bind to G protein-coupled receptors (GPCRs) act as guanine nucleotide exchange factors (GEFs) for the heterotrimeric G proteins.
When the GDP on the Gα subunit is replaced with GTP, the complex dissociates into Gα/GTP and Gβγ subunits that are then capable of activating
or inhibiting a wide range of signalling systems. Most of the actions are stimulatory, but some are inhibitory, as illustrated by the yellow arrows. The
regulators of G protein signalling (RGS) proteins function as GTPase-activating proteins (GAPs) to facilitate the GTPase activity of the Gα subunit,
which is the OFF reaction that terminates signalling. G protein receptor kinase (GRK) phosphorylates active receptors and provides binding sites for
arrestin that result in receptor desensitization by preventing the heterotrimeric G proteins from binding the receptor.

Ras signalling mechanisms of such RasGAPs include p120 RasGAP, neurofibromin,
Ras is a small (21 kDa) GTPase that plays a central role SynGAP, Ca 2 + -promoted Ras inactivator (CAPRI) and
as a signal transducer for a number of signalling sys- Ras GTPase-activating-like (RASAL). The function of
tems. It was first identified as a transducer for the tyr- some of these RasGAPs such as CAPRI and RASAL are
osine kinase-linked receptors (Module 1: Figure stimuli attracting considerable attention because they are Ca 2 + -
for enzyme-linked receptors), where it functions to re- sensitive proteins that rapidly translocate to the mem-
lay information to the mitogen-activated protein kinase brane through their C2 domains whenever there is an in-
(MAPK) signalling pathway. It is now known that ac- crease in the level of Ca 2 + . SynGAP, which is expressed
tivated Ras is able to relay information to a number of mainly in brain, is also activated by Ca 2 + following its
other signalling pathways. Like other G proteins (Module phosphorylation by Ca 2 + /calmodulin-dependent protein
2: Figure G protein binary switching), Ras functions as kinase II (CaMKII). The role of Ca 2 + in modulating the
a binary switch that is activated by binding GTP. There activity of both the RasGEFs and RasGAPs indicates an
are thus two critical aspects to Ras action: how is the important feedback interaction between the Ca 2 + and Ras
switch controlled and how is information relayed out to signalling pathways.
different signalling pathways (Module 2: Figure Ras sig- The Ras signalling mechanism relays information to a
nalling)? With regard to the first question, the ON reac- number of signalling targets:
tion of the binary switch is controlled by a number of Ras
guanine nucleotide exchange factors (RasGEFs) such as • It activates Raf to initiate the MAPK signalling pathway
Son-of-sevenless (SoS), Ras guanine nucleotide release-in- (Module 2: Figure ERK signalling).
ducing factors (RasGRFs) and Ras guanine nucleotide • It activates phospholipase Cε (PLCε) (Module 2: Figure
releasing proteins (RasGRPs) (Module 2: Table mono- PLC structure and function).
meric G protein toolkit). This conversion of Ras·GDP into • It activates the PtdIns 3-kinase signalling pathway.
Ras·GTP is inhibited by the tumour suppressor protein • Ras can activate a family of RalGEFs such as Ral-
merlin. Neurofibromatosis type 2 is caused by mutations GDP dissociation stimulator that then activates the Ral
in merlin. proteins (RalA and RalB) (Module 2: Figure Ras sig-
There are a number of Ras GTPase-activating proteins nalling). One of the functions of RalA is to stimulate the
(RasGAPs) that accelerate the OFF reaction by speed- phospholipase D signalling pathway (Module 2: Figure
ing up the hydrolysis of GTP to GDP by Ras. Examples PLD signalling).

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