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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 15

Module 2: Figure Rac signalling

Rac responses
Stimulus Stimulus
NOX ROS signalling
PTKR GPCR Ca 2+
+
Arf6
PIP
Ca 2+ TK TK 3 CIB1 Cofilin
P
DOCK Actin
CaMKII Kalirin 180 Vav1 Sos GEFs disassembly
TIAM P-Rex PAK1 LIM-K1 Cofilin
P
Rac GTP GDP Rac
GDP GTP Actin
IRS p53 WAVE Arp2/3 assembly
Actin
3BP-1 GAPs PtdIns4P polymerization
PtdIns4P Actin-Profilin
5-kinase Profilin
PtdIns4,5P 2

Function of the Rac monomeric G protein in signal transduction.
Rac is inactive when bound to GDP, but switches into an active form when this GDP is exchanged for GTP. This GTP for GDP exchange is facilitated by
a number of guanine nucleotide exchange factors (GEFs) such as Tiam, Kalirin, Vav, SoS and P-Rex, which are sensitive to various messengers such
as Ca 2 + , PtdIns3,4,5P 3 (PIP 3 )orGβγ subunits of heterotrimeric G proteins. The activated Rac/GTP then relays information out to different signalling
pathways as described in the text. Further details concerning the role of Wiskott--Aldrich syndrome protein (WASP) verprolin homologous (WAVE) are
shown in Module 4: Figure actin remodelling.

during spine morphogenesis (Module 10: Figure post- p115-RhoGEF and PDZ-RhoGEF are specific for coup-
synaptic density) and during the Ca 2 + and synaptic ling G-protein-coupled receptors (GPCRs) to Rho activa-
plasticity changes that occur during long-term poten- tion. Net-1, which appears to be sensitive to PtdIns3,4,5P 3
tiation (LTP) (Module 10: Figure Ca 2 + -induced syn- (PIP 3 ), is normally found in the nucleus, but translocates
aptic plasticity). to the cytoplasm, where it functions to activate RhoA. An-
other important GEF is Ect2, which is also found in the
Rho signalling mechanisms nucleus during interphase, but then associates with micro-
The Rho (Ras homologue) signalling pathway has an im- tubules during mitosis, where it stimulates the activation
portant role in regulating a number of systems, in par- of Rho cytokinesis (Module 9: Figure cytokinesis).
ticular the operation of the cytoskeleton. It regulates the The activated Rho/GTP complex is able to stimulate a
function of actin in two main ways. Firstly, it controls number of signalling processes, many of which are directed
some of the processes that function in actin assembly and towards remodelling of actin and its contraction. Many of
it also operates one of the control mechanisms that regulate the actions of Rho are carried out through a Rho kinase
the myosin II--actin interaction responsible for contraction (ROK). Diaphanous-related forming 1 (Dia1) is one of
both in smooth muscle cells and non-muscle cells (Module the downstream effectors that responds to Rho/GTP by
2: Figure Rho signalling). Like other G proteins, Rho func- interacting with profilin to increase actin polymerization.
tions as a binary switch. It is inactive when bound to GDP, Oligophrenin-1 (OPHN1) is a Rho Gap that functions
but when this GDP is exchanged for GTP, the Rho/GTP to stabilize AMPA receptors at neuronal synapses and thus
complex becomes active. External stimuli can activate this plays an important role in both synapse formation and
switch using different Rho guanine nucleotide exchange synaptic plasticity. Mutations in the OPHN1 gene have
factors (RhoGEFs). There are a large number of such been linked to mental retardation.
RhoGEFs that are characterized by having a Dbl homo- The following are some examples of the function of Rho
logy (DH) domain. The term Dbl comes from diffuse B cell signalling:
lymphoma, which is the cell line where the first RhoGEF
was identified. The family of Dbl-containing GEFs has
now expanded to 69 members, some of which are shown • Activation of smooth muscle contraction (Module 7:
in Module 2: Table monomeric G protein toolkit.These Figure smooth muscle cell E-C coupling).
GEFs are not necessarily specific for Rho: some are rather • Assembly of the actomyosin contractile ring and
promiscuous and will also function as Rac and Cdc42 activation of the contraction during cytokinesis
GEFs. In the case of Rho, ephexin appears to be specific for (Module 9: Figure cytokinesis).
coupling ephrin receptors to Rho (Module 2: Figure Rho • Endothelial cell contraction to open the permeability
signalling). Also leukaemia-associated RhoGEF (LARG), barrier (Module 7: Figure endothelial cell contraction).

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