Rab GEFs and GAPs: The Enigma Variations - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 93

disorder Warburg Micro Syndrome (Liegel et al. 2013 ). TBC1D20 has also been
implicated in other forms of neurodegenerative disorder (Gitler et al. 2008 ). This
suggests that TBC1D20 function is essential for normal neuronal cell function, but
may be less critical in other cell types. In budding yeast Gyp1 acts as a GAP for
Ypt1 at the Golgi. In contrast to TBC1D20/Gyp8 which is an ER transmembrane
protein, Gyp1 is a peripheral membrane protein found at the Golgi (Du and Novick
2001 ; De Antoni et al. 2002 ; Haas et al. 2007 ). Rab1/Ypt1 may therefore be
regulated by a combination of both ER and Golgi GAPs.
Four TBC1 domain GAPs Gyp3/Msb3, Gyp4/Msb4, Gyl1/App2 and Gyp5 have
been implicated in the regulation of Sec4 in polarised growth of budding yeast
(Albert and Gallwitz 2000 ; Gao et al. 2003 ; Prigent et al. 2011 ; Chesneau
et al. 2004 ; Chesneau et al. 2008 ). Why so many GAPs are required for Sec4
regulation during polarised growth is unclear. Biochemical characterisation paints a
confusing picture of Gyp specificity, and Gyp3/Msb3 shows strong activity towards
both Sec4 and Rab5-related GTPases. Furthermore, Gyp3/Msb3 has also been
shown to act as a GAP for yeast Rab5-related GTPases during endosomal matura-
tion (Nickerson et al. 2012 ; Lachmann et al. 2012 ). In this case the BLOC-1
complex recruits Gyp3/Msb3 to the yeast vacuole and promotes its activity towards
Rab5 family GTPases (Nickerson et al. 2012 ; Lachmann et al. 2012 ). Therefore, in
budding yeast it appears that Gyps may have more than one target GTPase and the
specific site of action may be determined by additional regulatory factors. This may
be due to the need to integrate regulation of different trafficking pathways, for
example polarised growth with endocytosis; however this notion is speculative
at best.
Overexpression screening and subsequent biochemical analysis have provided a
clearer picture of the function of some human Rab-RabGAP pairs involved in
formation of polarised cell structures. The primary cilium is an important site of
signalling formed at the apical surface of many epithelial cell layers, and on
fibroblast cell lines in culture. A series of Rab-RabGAP pairs was identified for
the process of primary cilium formation in human cell lines (Yoshimura
et al. 2007 ). TBC1D30 is a GAP for Rab8 enriched at primary cilia, while EVI5-
like is the GAP for Rab23 known to modulate the Hedgehog signalling pathway at
cilia during development (Yoshimura et al. 2007 ). A second GAP for Rab8,
TBC1D17, has also been reported (Vaibhava et al. 2012 ). Intriguingly, TBC1D17
forms a complex with optineurin, and glaucoma-associated mutants in optineurin
appear to potentiate TBC1D17 inhibition of Rab8 (Vaibhava et al. 2012 ). In
addition to Rab8, Rab10 is an important regulator of transport in polarised cells
and is controlled by two GAPs TBC1D1 and TBC1D4 (Peck et al. 2009 ; Miinea
et al. 2005 ). These proteins are best characterised in terms of their function in the
glucose transporter recycling pathway, and have different regulatory properties.
TBC1D4 and TBC1D1 are regulated by the Akt and AMP-activated kinase signal-
ling pathways, respectively (Peck et al. 2009 ; Miinea et al. 2005 ). Therefore in this
instance multiple Rab GAPs are used so that specific signalling inputs can modulate
the activity of the target GTPase, rather than to create redundancy.