description
Human cells have more than 60 RAB proteins that are key regulators of intracellular membrane trafficking. These small GTPases contribute to trafficking specificity by localizing to the membranes of different organelles and interacting with effectors such as sorting adaptors, tethering factors, kinases, phosphatases and tubular-vesicular cargo (reviewed in Stenmark et al, 2009; Wandinger-Ness and Zerial, 2014; Zhen and Stenmark, 2015). RAB localization depends on a number of factors including C-terminal prenylation, the sequence of upstream hypervariable regions and what nucleotide is bound, as well as interaction with RAB-interacting proteins (Chavrier et al, 1991; Ullrich et al, 1993; Soldati et al, 1994; Farnsworth et al, 1994; Seabra, 1996; Wu et al, 2010; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014). More recently, the activity of RAB GEFs has also been implicated in regulating the localization of RAB proteins (Blumer et al, 2103; Schoebel et al, 2009; Cabrera and Ungermann, 2013; reviewed in Barr, 2013; Zhen and Stenmark, 2015)In the active, GTP-bound form, RAB proteins are membrane-associated, while in the inactive GDP-bound form, RABs are extracted from the target membrane and exist in a soluble form in complex with GDP dissociation inhibitors (GDIs) (Ullrich et al, 1993; Soldati et al, 1994; Gavriljuk et al, 2013). Conversion between the inactive and active form relies on the activities of RAB guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) (Yoshimura et al, 2010; Wu et al, 2011; Pan et al, 2006; Frasa et al, 2012; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014; Ishida et al, 2016).Newly synthesized RABs are bound to a RAB escort protein, CHM (also known as REP1) or CHML (REP2) (Alexandrov et al, 1994; Shen and Seabra, 1996). CHM/REP proteins are the substrate-binding component of the trimeric RAB geranylgeranyltransferase enzyme (GGTaseII) along with the two catalytic subunits RABGGTA and RABGGTB (reviewed in Gutkowska and Swiezewska, 2012; Palsuledesai and Distefano, 2015). REP proteins recruit the unmodified RAB in its GDP-bound state to the GGTase for sequential geranylgeranylation at one or two C-terminal cysteine residues (Alexandrov et al, 1994; Seabra et al 1996; Shen and Seabra, 1996; Baron and Seabra, 2008). After geranylation, CHM/REP proteins remain in complex with the geranylated RAB and escort it to its target membrane, where RAB activity is regulated by GAPs, GEFs, GDIs and membrane-bound GDI displacement factors (GDFs) (Sivars et al, 2003; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014).Unlike the RAB GAPS, which (to date) all contain a shared TBC domain, RAB GEFs are structurally diverse and range from monomeric to multisubunit complexes (reviewed in Fukuda et al, 2011; Frasa et al, 2012; Cherfils and Zeghouf, 2013; Ishida et al, 2016). While many GEFs contain one of three conserved GEF domains identified to date - the DENN (differentially expressed in normal and neoplastic cell) domain, the VPS9 domain and the SEC2 domain- other GEFs lack a conserved domain (reviewed in Ishida et al, 2016). Based on sequence conservation and subunit organization, GEFs can be grouped into 6 general classes: the DENND-containing GEFs, the VPS9-containing GEFs (both monomeric), the SEC2-containing GEFs (homodimeric), heterodimeric GEF complexes such as RIC1:RGP1, the multisubunit TRAPPC GEF, and others (reviewed in Barr and Lambright, 2010; Marat et al, 2011; Ishida et al, 2016). GEFs for many RABs have still not been identified, however

external resources
NCBI:1457806
REACTOME:R-HSA-8876198
PUBMED:23898197
PUBMED:16855591
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genes
AKT1 , AKT2 , CHM , CHML , GDI1 , GDI2 , HPS1 , RAB8A , RAB1A , RAB3A , RAB3IL1 , RAB5A , RAB5B , RAB6A , RAB13 , RAB27A , RAB27B , RAB5C , SBF1 , TRAPPC2 , ST5 , TRAPPC10 , YWHAE , RAB7A , ULK1 , MADD , RAB9A , RIN1 , RGP1 , DENND4B , AKT3 , DENND4A , RAB10 , RAB32 , RAB35 , RAB31 , TRAPPC8 , MON1B , DENND3 , RAB3GAP1 , RAB18 , RAB21 , DENND5A , RAB38 , RAB3GAP2 , GAPVD1 , TRAPPC3 , DENND2A , RABGEF1 , TRAPPC12 , RAB9B , TRAPPC4 , RAB14 , RAB6B , CCZ1 , TRAPPC2L , RAB8B , RIN2 , RAB39A , DENND4C , RIC1 , ALS2 , DENND1A , TRAPPC1 , TRAPPC11 , TRAPPC6A , RIN3 , DENND1C , DENND2D , TRAPPC13 , SBF2 , RAB1B , TRAPPC9 , ANKRD27 , MON1A , HPS4 , RAB39B , RAB3IP , TRAPPC6B , TRAPPC5 , RINL , DENND5B , DENND2C , DENND1B , RAB12 , DENND6A , CCZ1B , ALS2CL , DENND6B , MIR3656 ,