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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 16

Module 2: Figure Rho signalling

Rho responses
CaM
MLCK
Stimulus Stimulus Myosin II
MLC P Contraction
P
PPI
GPCR MYPT1
PTKR
PIP
3 PPI
12/13 P MYPT1
TK TK
ROK
Net1 LARG p115-RhoGEF
Ephexin
PDZ-RhoGEF
Cofilin
LIM-K1
PtdIns4P Actin
assembly
GTP GDP P
Rho Rho PtdIns4P Cofilin
GDP GTP 5-kinase
Actin
PtdIns4,5P 2 polymerization
DLC1 p190Rho
GAPs GAP
mDia
Profilin
Actin-Profilin
Function of the Rho monomeric G protein in cell signal transduction.
Rho is a typical G protein that is activated when GDP is exchanged for GTP. This exchange is facilitated by a number of Rho guanine nucleotide exchange
factors (RhoGEFs). For example, the ephexins mediate the action of protein tyrosine-linked receptors (PTKRs), such as the ephrin receptors, whereas
the G protein-coupled receptors (GPCRs) use the α 12/13 subunit of heterotrimeric G proteins to activate leukaemia-associated RhoGEF (LARG),
p115-RhoGEF or PDZ-RhoGEF. The activated Rho/GTP complex then activates a number of signalling systems as outlined in the text.

• Assembly of the actin ring in osteoclast podosomes of its main actions is to stimulate the Wiskott-Aldrich
(Module 7: Figure osteoclast podosome). syndrome protein (WASP) that acts on the actin-related
• Eph receptor-induced growth cone collapse in develop- protein 2/3 complex (Arp2/3 complex) to initiate actin
ing neurons (Module 1: Figure Eph receptor signalling). polymerization (Module 4: Figure actin remodelling). This
• Activation of uropod contraction during neutrophil action is facilitated by Cdc42 acting on profilin through in-
chemotaxis (Module 11: Figure neutrophil chemotactic sulin receptor substrate p53 (IRSp53) and Mena.
signalling). The Cdc42 signalling mechanism plays an important
• Physical interactions between endothelial cells and role in actin polymerization in synaptic spines as part of
the extracellular matrix (ECM) activate p190RhoGAP the events associated with Ca 2 + and synaptic plasticity
that is responsible for the mechanosensitive control of (Module 10: Figure Ca 2 + -induced synaptic plasticity).
VEGF receptor expression.
Arf signalling mechanisms
Cdc42 signalling mechanisms The ADP-ribosylation factors (Arfs) are best known for
The Cdc42 signalling mechanism has an important role their role in membrane and protein trafficking.There are
in controlling the actin cytoskeleton. It regulates some of six mammalian Arfs that are divided into three classes
the processes that function in actin assembly (Module 2: (Module 2: Table monomeric G-protein toolkit). The Class
Figure Cdc42 signalling). Like other G proteins, Cdc42 I and Class II Arfs are found mainly at the Golgi and
functions as a binary switch. It is inactive when bound also on various endosomal membranes where they func-
to GDP, but when this GDP is exchanged for GTP, the tion in actin remodelling and formation of the coat pro-
Cdc42/GTP complex becomes active. External stimuli ac- tein complexes responsible for the vesicle budding that
tivate this switch using different guanine nucleotide ex- transfers cargo form one compartment to another. Such
change factors (GEFs), such as intersectin-long (ITSN- aroleisevident in thecaseof COPI-mediated transport
L) and PAK-interacting exchange factor α (α-Pix). Just from Golgi to ER (Module 4: Figure COPI-coated ves-
how these Cdc42 RhoGEFs are activated is still not prop- icles). Class III has a single member Arf6, which func-
erly understood. In the case of the Ephrin (Eph) receptor tions at the plasma membrane where it can have marked
signalling pathway, intersectin is activated by binding to effects on actin polymerization. One action of Arf6 is to
the EphA receptor (Module 1: Figure Eph receptor sig- induce the trafficking of Rac1 to the plasma membrane
nalling). The activated Cdc42/GTP complex then stimu- where it is activated by the Rac GEF called downstream of
lates various elements that regulate actin polymerization. Crk-180 homologue (DOCK180) to increase membrane
It promotes actin stability by stimulating p21-activated ruffling and focal adhesion actin attachment (Module 6:
kinase (PAK) to phosphorylate LIM kinase, which phos- Figure integrin signalling). The DOCK180 acts as a com-
phorylates cofilin to inhibit its ability to cut actin. One plex in association with a protein called engulfment and

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