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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 11

Module 2: Figure Ras signalling

Glutamate Growth
factors
Ca 2+
Ras responses
NMDAR PTKR
2+ DAG
Ca
+ +
TK
TK
RasGRP
RasGRF SOS Raf ERK1/2
2+ CaM
Ca
PI 3-K PIP 3
+ 2+
Ras GTP GDP Ras InsP 3 Ca
PLC
GDP GTP DAG
NEUROFIBROMIN Ral-GDS Ral PLD1
RASAL
CAPRI p120
SynGAP
Ras GAP
CaMKII
+
+ GAPs
2+ +
Ca

Function of the monomeric Ras G protein in cell signal transduction.
Ras plays a role as a signal transducer to relay information from various external stimuli to a range of different Ras-dependent responses. When bound
to GDP, Ras is inactive. Cell stimuli act through different guanine nucleotide exchange factors (GEFs) such as Son-of-sevenless (SoS), RasGRF and
RasGRP to facilitate an exchange of GDP for GTP to create the activated Ras/GTP complex that can relay information through a number of signalling
pathways. The action of Ras is terminated by a variety of GTPase-activating proteins (GAPs) that accelerate the ability of Ras to hydrolyse GTP back
to GDP.

Son-of-sevenless (SoS) and thus responds to the microdomain of Ca 2 + near the
Son-of-sevenless (SoS) is a classical Ras guanine nucle- mouth of the channel. This signalling mechanism func-
otide exchange factor (RasGEF). Its mode of action is tions in neuronal gene transcription (Module 10: Figure
evident in the way the platelet-derived growth factor re- neuronal gene transcription).
ceptor (PDGFR) is linked to the mitogen-activated pro-
tein kinase (MAPK) signalling pathway (Module 1: Fig- Ras guanine nucleotide releasing proteins (RasGRPs)
ure PDGFR activation). SoS binds to the Src homology 3 The Ras guanine nucleotide releasing proteins (RasGRPs)
(SH3)-containing adaptor growth factor receptor-bound are mainly expressed in haematopoietic cells (Module 2:
protein 2 (Grb2), which is attached to the phosphotyr- Table monomeric G protein toolkit). These GRPs are also
osine residues of the activated receptor. Once it is associ- known as CalDAG-GEFs because they are sensitive to di-
ated with the receptor, SoS comes into contact with Ras acylglycerol (DAG) and Ca 2 + . They contain a C1 domain
and can begin to facilitate the exchange of GDP for GTP, that binds DAG and they also have a pair of Ca 2 + -binding
thus creating the active Ras/GTP complex that begins to EF-hands. The sensitivity to both DAG and Ca 2 + sug-
stimulate the MAPK signalling pathway (for further de- gests that these RasGRPs may couple phosphoinositide
tails see Module 2: Figure ERK signalling). signalling to the activation of the various pathways that
are linked to Ras (Module 2: Figure Ras signalling).
Ras guanine nucleotide release-inducing factors
(RasGRFs) Rap signalling mechanisms
The Ras guanine nucleotide release-inducing factors The Ras-related protein (Rap) family are typical small
(RasGRFs) and Ras guanine nucleotide releasing proteins monomeric G-proteins that belong to the Ras superfam-
(RasGRPs) are also important GEFs that can relay inform- ily (Module 2: Table monomeric G-protein toolkit). The
ation to Ras. The RasGRFs, which are strongly expressed Rap family has four members Rap1A, Rap1B, Rap2A and
in brain, are particularly important for the activation of Rap2B. One of the guanine nucleotide-exchange factors
the MAPK signalling pathway in neurons, where they re- (GEFs) is the cyclic AMP-dependent GEF EPAC that
spond to activation of N-methyl-D-aspartate (NMDA) re- regulates the activation of Rap1 and Rap2B. This pathway
ceptors. One of the functions of the latter is to gate Ca 2 + , can activate phospholipase Cε (PLCε) (Module 2: Figure
which then acts through calmodulin (CaM) to stimulate cyclic AMP signalling). Such a mechanism has been im-
RasGRF. This is a highly localized signalling event, be- plicated in the control of autophagy (Module 11: Figure
cause the RasGRF is associated with the NMDA receptor autophagy).

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