Page 12 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 12

Module 2: Figure Rab signalling

Rab responses

GDI Arf1 Coat assembly,
GBF1 cargo selection,
Rab p115 budding
GDP
GDF Bicaudal D1
GEFs
Rab membrane Dynein
cycle Rabex-5 Rabin3
TRAPP1 Motility
FIP2
GDI
Myrip Myosin V
Rab GTP GDP Rab Melanophilin
GDP Rab GTP/GDP GTP
GGT cycle PtdIns3P
Geranylgeranyl
groups Rin1 PtdIns hVPS34
Tbc1d1 Rab3GAP
Tbc1d4/ GAPs EEA1 Vesicle
AS160 docking/tethering
Rab REP
Rabankyrin-5
GDP
PKB PIP
3
REP SNARE Vesicle
PI 3-kinase p115 fusion
Rab
GDP Insulin
Function of the Rab monomeric G-protein in cell signalling.
The monomeric Rab G-protein is regulated at a number of levels. Newly synthesized Rab bound to GDP is recognized by the Rab escort protein
(REP), which presents it to the geranylgeranyl transferase (GGT). GGT adds geranylgeranyl groups to one or two of the C-terminal cysteine residues.
The geranylgeranylated Rab is recognized by the Rab GDP dissociation inhibitor (GDI), which operates the Rab membrane cycle. The Rab.GDP is
then targeted to specific membrane sites by interacting with the GDI displacement factor (GDF). Various guanine nucleotide-exchange factors (GEFs)
and GTPase-activating proteins (GAPs) operate the Rab GTP/GDP cycle responsible for the inter-conversions between inactive Rab.GDP and active
Rab.GTP. The latter then acts on a variety of effectors to regulate many of the processes responsible for protein trafficking.

Rab signalling mechanism Rab.GDP/GDI complex is then targeted to specific mem-
The Ras-associated binding (Rab) proteins are typical brane sites by interacting with the GDI displacement
small monomeric G-proteins that belong to the Ras super- factor (GDF). Once Rab has performed its function it
family. The primary function of the Rabs is to control mul- is extracted from the membrane by GDI and remains
tiple phases of membrane and protein trafficking such as in the cytosol until it is required again to carry out the
vesicle formation, motility, tethering and fusion to the ac- same or some other function. Some patients with X-linked
ceptor membrane and signalling to other organelles. There non-specific mental retardation have mutations in one of
are more than 60 human Rabs (Module 2: Table mono- the genes for GDI.
meric G-protein toolkit). The enormous proliferation of Rabs carry out their multiple tasks through the oper-
this family reflects their central role in the regulation of so ation of the Rab GTP/GDP cycle regulated by the co-
many vesicle trafficking processes. ordinated activity of guanine nucleotide-exchange factors
The continuous cycling between the cytosol and dif- (GEFs) and GTPase-activating proteins (GAPs) (Module
ferent membrane-bound compartments is shepherded by 2: Figure Rab signalling). Examples of the RAB GEFs in-
a number of protein factors and also requires the pren- clude Rabex-5, Rabin3 and TRAPP1. Examples of some of
ylation of Rab. This post-translational lipid modification the Rab GAPs are Rab3GAP, Rin1, Tbc1d1 and Tbc1d4
depends on the addition of isoprenes, which are intermedi- (also known as AS160). Tbc1d1 and Tbc1d4/AS160 are
aries in cholesterol biosynthesis. Following its synthesis, the targets of insulin action resulting in insertion of
Rab is bound to GDP and is soluble in the cytoplasm GLUT4-containing vesicles in skeletal muscle (Module
(Module 2: Figure Rab signalling). This Rab.GDP is then 7: Figure skeletal muscle E-C coupling). The Rab.GTP
recognized by the chaperone protein Rab escort protein form has the dynamic conformation and mobility to
(REP), which transfers it to the Rab geranylgeranyl trans- interact with many different downstream effectors that
ferase (GGT) that adds either one or two geranylgeranyl drive the multiple Rab responses (Module 2: Figure Rab
groups to cysteine residue(s) located at the C-terminus of signalling).
the Rab. Mutation of REP causes choroideraemia,aform An allele of Tbc1d4, which reduces the trans-
of blindness resulting from degeneration of the retinal pig- location of GLUT4 to the plasma membrane of
ment epithelium. skeletal muscle (Module 7: Figure skeletal muscle
The prenylated Rab enters the Rab membrane cycle E-C coupling), is linked to a susceptibility to
by binding to the GDP dissociation inhibitor (GDI). The obesity.

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