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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 17

Module 2: Figure Cdc42 signalling

Stimulus Stimulus

PTKR Cdc42 responses
GPCR
PIP
3
TK TK ? P Cofilin
ITSN-L Dbs
-Pix GEFs
PAK4 LIM-K1 Cofilin

Cdc42 GTP GDP Cdc42
GDP GTP
WASP Actin
assembly
Arp2/3
GAPs Actin
IRS p53
polymerization
Actin-Profilin
Profilin

Function of the Cdc42 monomeric G protein in signal transduction.
When bound to GDP, Cdc42 is inactive, but it is activated when the GDP is exchanged for GTP. This exchange is accelerated by guanine nucleotide
exchange factors (GEFs), but how these are activated is still somewhat of a mystery. The primary action of the Cdc42/GTP complex is to stimulate
actin assembly by inhibiting the action of cofilin, by promoting actin polymerization by acting on actin/profilin and Wiskott--Aldrich syndrome protein
(WASP). Further details on the role of WASP are shown in Module 4: Figure actin remodelling.

cell motility (ELMO). Arf6 has also been implicated in Another group of Arf GAPs with ANK repeats and PH
the endocytosis of AMPA receptors during the process domain (AZAPs) have 12 genes that fall into four groups
of Ca 2 + -induced synaptic plasticity at synaptic endings and the ‘Z’ refers to the protein domain that characterizes
(See step 4 in Module 10: Figure Ca 2 + -induced synaptic each subgroup:
plasticity). This function of Arf6 depends on the activity
of BRAG2, which is an Arf GEF that binds to the Glu2 • Arf GAP with coiled-coil, ANK repeats and PH domain
subunit of the AMPA receptor. (ACAP)
Like other monomeric GTP-binding proteins (G- • Arf GAP with GLD domain, ANK repeats and PH
proteins), Arf activity is regulated by a balance between domain (AGAP)
Arf guanine nucleotide-exchange factors (Arf GEFs) and • Arf GAP with Rho GAP, ANK repeats and PH domain
the Arf GTPase-activating proteins (Arf GAPs) (Module (ARAP)
2: Figure Arf signalling). Examples of Arf GEFs are Golgi- • Arf GAP with Src homology 3, ANK repeats and PH
specific brefeldin A resistant factor 1 (GBF1) and Arf domain (ASAP)
nucleotide-binding site opener (ARNO). These activation The ASAP family has three genes (ASAP1--3). The
mechanisms are counteracted by the Arf GAPs that facil- ASAP3--Arf6 complex is of interest because it is sensitive
itate the hydrolysis of GTP to GDP thus converting the to Ca 2 + that binds to a specific region at the complex
complex back into its inactive Arf.GDP state. There are 24 interface. This sensitivity to Ca 2 + suggests that there
human genes coding for Arf GAPs, which are character- may be cross-talk between the Arf and Ca 2 + signalling
ized by having an Arf GAP domain, that can be separated pathways.
into two main groups: the Arf GAP1 type and the Arf GAP To carry out its role in vesicle trafficking, the Arfs have
with ANK repeats and PH domain (AZAPs) (Module 2: two main actions. First, they catalyse the nucleation and
Table monomeric G protein toolkit). assembly of coat protein complexes during the process
The Arf GAP1 group has three genes coding for Arf of vesicle budding. This role is particularly evident at the
GAP1-3, two genes for stromal membrane-associated pro- Golgi during the formation of COPI vesicles (Module 4:
tein 1 and 2 (SMAP1 and SMAP2) and two genes coding Figure COPI-coated vesicles). The Arfs also play a role in
for G-protein-coupled receptor kinase interactors 1 and recruiting various Arf-associated golgins, such as GMAP-
2 (Git1 and Git2). ArfGAP1 and ArfGAP2/3 inactivates 210, to the Golgi membrane.
Arf1.GTP resulting in the shedding of the COPI coat as The Arfs also function by activating the PtdIns4,5P 2 sig-
the vesicles approach the endoplasmic reticulum (See step nalling cassette responsible for controlling multiple func-
7in Module 4: Figure COPI-coated vesicles). tions (Module 2: Figure PtdIns4,5P 2 signalling). The Arfs

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