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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 13

Rab1 Rab6
Rab1 functions in vesicle tethering and fusion especially During the process of COPII-mediated transport from
during both ER-to-Golgi and Golgi-to-ER transport (see ER to Golgi (Module 4: Figure COPII-coated vesicles),
steps 1 and 2 in Module 4: Figure membrane and protein Rab6 binds to Bicaudal D and thus provides a mechanism
trafficking). During the COPII-mediated transport from to attach the dynein motor complex to the vesicle for its
the ER to the Golgi (Module 4: Figure COPII-coated transfer between the ER and Golgi membranes (Module
vesicles), TRAPP1 is the guanine nucleotide-exchange 4: Figure dynein)
factor (GEF) that converts inactive Rab1.GDP into act-
ive Rab1.GTP during vesicle tethering prior to fusion Rab 7
to the Golgi membrane. The transport from the Golgi The two Rab7 proteins (Rab7A and Rab7B), which are
back to the ER begins with the golgin protein p115 re- expressed ubiquitously, play a role in regulating vesicle
cruiting Rab1b, which then activates the Golgi-specific trafficking between the endocytic and autophagic com-
brefeldin A resistant factor 1 (GBF1), which is a guan- partments. Rab7 is found on the acidic and degradative
ine nucleotide-exchange factor (GEF) for the small mono- organelles, such as the late endosomes, lysosomes, mul-
meric G-protein ADP-ribosylation factor 1 (Arf1) that has tivesicular bodies, phagosomes and autophagolysosomes.
an important role in controlling key events such as coat These mechanisms regulate the degradation of endocytic
formation, actin polymerization and Golgi vesicle bud- cargos such as EGF receptors and neurotrophic factor re-
ding during COPI-mediated transport from the Golgi to ceptors such as TrkA and internalized cholesterol. The role
the ER (Module 4: Figure COPI-coated vesicles). of RAB7 in lysosomal transport depends on the effector
protein Rab7-interacting lysosomal protein (RILP). Rab7
may also play a role in the retrograde trafficking of the
Rab3
signalling endosomes that supply trophic support to peri-
There are three Rab3 proteins (Rab3A, Rab3B, Rab3C and
pheral neurons.
Rab3D) that function in regulated exocytosis. These Rab3
Charcot-Marie-Tooth disease type 2B is caused by
members tend to be restricted to cells types with high rates
mutations in Rab7A.
of exocytosis such as neurons and neuroendocrine cells
(Rab3A and Rab3C). Rab3B is located on tight junctions Rab8
and secretory granules in epithelial cells. The more widely Rab8A interacts with myosin Vb to carry out non-
expressed Rab3D is located on the secretory granules of clathrin-dependent endocytosis. It also plays a role in the
non-neuronal cells such as fat cells, adipocytes, exocrine biogenesis of cilia by interacting with cenexin/ODF2.
glands and certain haematopoietic cells. Rab3A and Rab3C A defect in the transcriptional regulation of Rab8A has
tend to reduce exocytosis, whereas Rab3B and Rab3D have been linked to Microvillus inclusion disease.
a more positive role.
The activation of these Rabs is regulated by a Rab3GAP Rab11
which has two components: a catalytic RabGAP1 sub- There are three Rab11 proteins (Rab11A, Rab11B and
unit and a non-catalytic RabGAP2 subunit. Mutations in Rab11C), which function in both endocytic recycling and
RabGAP1 have been linked to Warburg Micro syndrome cytokinesis. Rab11 plays an important role in the trans-
whereas a milder form called Martsolf syndrome is cause port of synaptic vesicles where it is attached to myosin
by mutations in RabGAP2. Vb through the Rab11-family interacting proteins (FIPs)
(Module 4: Figure myosin motor). Such trafficking events
leading to receptor insertion are key components in the
Rab4
relationship between Ca 2 + and synaptic plasticity during
Rab 4, together with myosin V, functions in early endo-
the process of learning (Module 10: Figure Ca 2 + -induced
some to plasma membrane trafficking (Module 4: Figure
synaptic plasticity).
early endosome budding). Rab 4, together with myosin V,
Rab11, together with its effector FIP2, also plays a role
also functions in early endosome to trans-Golgi network
in the trafficking and insertion of aquaporin-2 (AQP2)
(TGN) trafficking (Module 4: Figure early endosome bud-
(Module 7: collecting duct function) and also plays a role
ding).
in controlling the trafficking and insertion of new vesicles
to form the cleavage furrow during cytokinesis (Module
Rab5 9: Figure cytokinesis).
Rab5 plays a role in endosome vesicle fusion to early endo-
somes by targeting vesicles to the early endosome (Module Rab27
4: Figure endosome vesicle fusion). Such a role is mani- There are two Rab27 proteins (Rab27A and Rab27B),
fest during phagosome maturation (Module 4: Figure pha- which function in intracellular transport of secretory gran-
gosome maturation). Rab5 also has a role in activating ules and melanosomes (Module 4: Figure myosin mo-
hVPS34 to promote vesicle nucleation during autophagy tor). Rab27 exerts its actions through various effectors
(Module 11: Figure autophagy signalling mechanisms). that fall into three families that have distinct functions.
Rabex-5 is the guanine nucleotide-exchange factor There are synaptotagmin-like proteins (Slps), Slp lacking
(GEFs) that activates Rab5, which then interacts with the C2 domains (Slac2s) and the Rab3-binding domain (RBD)
effector Rabaptin-5. Rab22 may play a role in recruiting family. They all have an N-terminal Rab27-binding do-
Rabex-5 to the early endosome. main known as the Slp-homology domain (SHD), which

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