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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 18

Module 2: Figure Arf signalling

Arf responses

Brefeldin A (BFA)
Nucleation and assembly of
coat protein complexes
Rab1
GEFs Cortactin
GBF1 ARNO
PtdIns
PtdIns4K
II
Arf GTP GDP Arf
GDP GTP PtdIns4P Actin Vesicle
polymerization budding
AGAPs
ACAPs
Arf GAPs ASAPs PtdIns4P
Git1/2 ARAPs 5-kinase
PtdIns4,5P
GAPs 2

PC PLD PA

Function of the Arf monomeric G-protein in signal transduction
When bound to GDP, Arf 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. In some cases, such as Golgi-specific brefeldin A resistant
factor 1 (GBF1), activation depends on other G-proteins such as Rab1 (Module 4: Figure COPI-coated vesicles). The primary action of the Arfs is to
stimulate actin polymerization and membrane remodelling during protein trafficking.

act by recruiting and stimulating both PtdIns 4 kinase p21-activated kinase (PAK)
IIIβ and the PtdIns4P 5-kinase (Module 2: Figure Arf sig- The p21-activated kinases (PAKs) are some of the major
nalling). All of the Arfs are responsible for phospholipase downstream targets of Rac and Rho (Module 2: Figure
D (PLD) activation (Module 2: Figure PLD signalling). Rho-regulated kinases). They have been implicated in a
The subsequent formation of phosphatidic acid (PA), large number of processes such as actin remodelling, cell
which is a bioactive lipid, has two actions: it acts syn- cycle control, transcription and apoptosis. There are six
ergistically to stimulate PtdIns4P 5-kinase and it alters isoforms (PAK1--PAK6) with slightly different functions.
membrane curvature during vesicle budding (Module 2: Rac acts through LIM kinase 1 (LIMK1) to phosphorylate
Figure Arf signalling). cofilin (Module 2: Figure Rac signalling). Rho acts through
PAK4 to phosphorylate the same LIMK1 (Module 2: Fig-
ure Cdc42 signalling). Another function of PAK1 is to
Dedicator of cytokinesis 8 (DOCK8)
phosphorylate myosin light chain kinase (MLCK), result-
There is a family of eleven dedicator of cytokinesis ing in a decrease in the activity of the actin--myosin con-
(DOCK) proteins that are guanine nucleotide-exchange tractile system. PAK1 can also be activated independently
factors (GEFs) that appear to act primarily on the Rac sig- of Rac through the calcium and integrin-binding protein 1
nalling mechanism and the Cdc42 signalling mechanism. (CIB1) that acts by stimulating PAK1 (Module 2: Figure
A typical example is DOCK8, which has an N-terminal Rac signalling).
DOCK Homology Region-1 (DHR-1) responsible for the The fragile X mental retardation protein 1 RMRP1,
guanine nucleotide-exchange reaction and a C-terminal which is mutated in fragile X syndrome (FXS),may
DHR-2 domain that is thought to bind phospholipids. act to inhibit the function of PAK particularly during
This family of DOCK proteins may act by remodelling
actin remodelling in neuronal spines (Module 10: Figure
actin to carry out a variety of cellular functions such as the
Ca 2 + -dependent synaptic plasticity).
control of cell migration, morphology, adhesion and pro-
liferation. During the process of B-cell differentiation in
the lymph node, DOCK8 is activated following its inter- Myotonic dystrophy kinase-related Cdc42-binding
action with the integrin intercellular adhesion molecule 1 kinase (MRCK)
(ICAM1) (Module 8: Figure B cell maturation signalling). Myotonic dystrophy kinase-related Cdc42-binding kinase
Loss-of-function mutations in DOCK8 have been (MRCK) has a number of functional domains and be-
linked to variants of hyper-IgE syndromes (HIES) and longs to the same family as Rho kinase (ROK) (Module
mental retardation. 2: Figure Rho-regulated kinases). MRCK, which is

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