RAB3IP is a GEF for RAB8A, the only RAB GTPase localized in the cilium. GTP-bound RAB8A may play a role in recruiting vesicles from the Golgi to the ciliary base and is required for cilia formation (Nachury et al, 2007; Yoshimura et al, 2007; reviewed in Reiter et al, 2012).

Once recruited to the ciliary targeting complex, RAB3IP/RABIN8 stimulates nucleotide exchange on RAB8A. Activated RAB8A is required for ciliogenesis and plays a role in mediating vesicle docking at the basal body, providing both lipid and protein content to the emerging cilium (Hattula et al, 2002; Knodler et al, 2010; Nachury et al, 2007; Wang et al, 2012; Westlake et al, 2011; Yoshimura et al, 2007; reviewed in Deretic, 2013; Sung and Leroux, 2013).

RAB8A is another small GTPase that is required for ciliogenesis. RAB8A is recruited to the ciliary targeting complex at the trans-Golgi network (TGN) through interactions of the RAB8A guanine nucleotide exchange factor (GEF) RAB3IP (also known as RABIN8) with ASAP1 and RAB11 (Wang et al, 2012; Westlake et al, 2011; Feng et al, 2012; reviewed in Deretic, 2013). RAB8A is recruited in the inactive GDP bound form, and is activated at the TGN by RAB3IP in a RAB11A-dependent fashion (Hatulla et al, 2002; Knodler et al, 2010; Westlake et al, 2012; Wang et al, 2012; Feng et al, 2012).

RAB proteins have intrinsic weak GTPase activity that is enhanced by RAB-GTPase activating proteins (RAB-GAPs, Sano et al. 2007). The GTPase activity of RAB13 is inferred from other RAB proteins. AS160 (TBC1D4) and TBC1D1 are GAPs that activate the GTPase activity of RAB8A/10/13. Insulin signaling activates AKT, which phosphorylates and inactivates AS160 and TBC1D1, allowing GTP-bound (active) RABs to accumulate.
The GAP domain of TBC1D4 (AS160) activates the GTPase activity of RAB proteins (Sano et al. 2007). The effect of TBC1D4 on RAB13 is inferred from rat muscle cells (Sun et al. 2010).
As inferred from mouse, TBC1D1 activates GTPase activity of RAB2A, 8A, 8B, 10, and 14 (Roach et al. 2007).

RAB8A/10/13/14 release GDP and bind GTP to yield the active complex. Guanine nucleotide exchange factors (GEFs) stimulate the reaction. GTPase-activating proteins (GAPs) oppose the reaction by stimulating the intrinsic GTPase activity of the RAB proteins.

TBC1D10A (EPI64) stabilizes active ARF6 and also has an additional function in the ARF6-dependent pathway through regulating the levels of active RAB8A. RAB8A is involved in the recycling pathway from endosomes back to the plasma membrane. TBC1D10A binds the Rab8a effector JFC1 and reduces the level of Rab8a:GTP to regulate Rab8a/Arf6-dependent membrane trafficking. TBC1D10A binds JFC1 through its (Slp) homology domain (SHD), and JFC1 can simultaneously interact with active Rab8a (Hokanson & Bretscher 2011).

In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 (SLC2A4) glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011, Jaldin-Fincati et al. 2017). In myocytes muscle contraction alone can also cause translocation of GLUT4.
Though the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins.
Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane.

Proteomic studies suggest that the cilium is home to approximately a thousand proteins, and has a unique protein and lipid make up relative to the bulk cytoplasm and plasma membrane (Pazour et al, 2005; Ishikawa et al, 2012; Ostrowoski et al, 2002; reviewed in Emmer et al, 2010; Rohatgi and Snell, 2010). In addition, the cilium is a dynamic structure, and the axoneme is continually being remodeled by addition and removal of tubulin at the distal tip (Marshall and Rosenbaum, 2001; Stephens, 1997; Song et al, 2001). As a result, the function and structure of this organelle relies on the directed trafficking of protein and vesicles to the cilium. Small GTPases of the RAS, RAB, ARF and ARL families are involved in cytoskeletal organization and membrane traffic and are required to regulate the traffic from the Golgi and the trans-Golgi network to the cilium (reviewed in Deretic, 2013; Li et al, 2012). ARF4 is a Golgi-resident GTPase that acts in conjunction with a ciliary-targeting complex consisting of the ARF-GAP ASAP1, RAB11A, the RAB11 effector FIP3 and the RAB8A guanine nucleotide exchange factor RAB3IP/RABIN8 to target cargo bearing a putative C-terminal VxPx targeting motif to the cilium. A well-studied example of this system involves the trafficking of rhodopsin to the retinal rod photoreceptors, a specialized form of the cilium (reviewed in Deretic, 2013). ARL3, ARL13B and ARL6 are all small ARF-like GTPases with assorted roles in ciliary trafficking and maintenance. Studies in C. elegans suggest that ARL3 and ARL13B have opposing roles in maintaining the stability of the anterograde IFT trains in the cilium (Li et al, 2010). In addition, both ARL3 and ARL13B have roles in facilitating the traffic of subsets of ciliary cargo to the cilium. Myristoylated cargo such as peripheral membrane protein Nephrocystin-3 (NPHP3) is targeted to the cilium in a UNC119- and ARL3-dependent manner, while ARL13B is required for the PDE6-dependent ciliary localization of INPP5E (Wright et al, 2011; Humbert et al, 2012; reviewed in Li et al, 2012). ARL6 was also identified as BBS3, a gene that when mutated gives rise to the ciliopathy Bardet-Biedl syndrome (BBS). ARL6 acts upstream of a complex of 8 other BBS-associated proteins known as the BBSome. ARL6 and the BBSome are required for the ciliary targeting of proteins including the melanin concentrating hormone receptor (MCHR) and the somatostatin receptor (SSTR3), among others (Nachury et al, 2007; Loktev et al, 2008; Jin et al, 2010; Zhang et al, 2011). Both the BBSome and ARL6 may continue to be associated with cargo inside the cilium, as they are observed to undergo typical IFT movements along the axoneme (Fan et al, 2004; Lechtreck et al, 2009; reviewed in Li et al, 2012).