Reactome: A Curated Pathway Database

HPS1:HPS4 exchange GTP for GDP on RAB32 and RAB38

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

RAB32 and RAB38 play non-redundant but overlapping roles in melanosome and lysosome-related organelle (LRO) biogenesis (Loftus et al, 2002; Wasmeier et al, 2006; Lopes et al, 2007; Wang et al, 2008; Bultema et al, 2012; reviewed in Bultema and di Pietro, 2012). Through interaction with effector protein ANKRD27 (also known as VARP, a RAB21-specific GEF), RAB32 and RAB38 control trafficking of melanogenic enzymes; ANKRD27 GEF activity does not appear to be essential for this, however (Tamura et al, 2009; Tamura et al, 2011; Ohbayahsi et al, 2012). BLOC-3, a dimeric complex of HPS1 and HPS4, has RAB32- and RAB38 GEF activity and mutation in the genes encoding HPS1 and HPS4 results in defects in pigmentation and mislocalization of RAB32 and 38, and are associated with the rare autosomal recessive disorder Hermansky-Pudlak Syndrome (Gerondopoulos et al, 2012; reviewed in Ishida et al, 2016). Interaction of RAB32:GDP or RAB38:GDP with BLOC-3 promotes release of GDP, allowing GTP to bind, and precludes the interaction of the RAB proteins with GDI and CHM proteins.

Literature References
PubMed ID Title Journal Year
22171327 The Rab21-GEF activity of Varp, but not its Rab32/38 effector function, is required for dendrite formation in melanocytes Mol. Biol. Cell 2012
17043139 Rab38 and Rab32 control post-Golgi trafficking of melanogenic enzymes J. Cell Biol. 2006
17671165 Melanosome maturation defect in Rab38-deficient retinal pigment epithelium results in instability of immature melanosomes during transient melanogenesis Mol. Biol. Cell 2007
23084991 BLOC-3 mutated in Hermansky-Pudlak syndrome is a Rab32/38 guanine nucleotide exchange factor Curr. Biol. 2012
11917121 Mutation of melanosome protein RAB38 in chocolate mice Proc. Natl. Acad. Sci. U.S.A. 2002
22511774 BLOC-2, AP-3, and AP-1 proteins function in concert with Rab38 and Rab32 proteins to mediate protein trafficking to lysosome-related organelles J. Biol. Chem. 2012
21187289 Structure-function analysis of VPS9-ankyrin-repeat protein (Varp) in the trafficking of tyrosinase-related protein 1 in melanocytes J. Biol. Chem. 2011
23247405 Cell type-specific Rab32 and Rab38 cooperate with the ubiquitous lysosome biogenesis machinery to synthesize specialized lysosome-related organelles Small GTPases 2013
19403694 Varp is a novel Rab32/38-binding protein that regulates Tyrp1 trafficking in melanocytes Mol. Biol. Cell 2009
27246931 Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases Cell Struct. Funct. 2016
18477474 Varp interacts with Rab38 and functions as its potential effector Biochem. Biophys. Res. Commun. 2008
Participant Of
This entity is regulated by:
Title Physical Entity Activity
Rab guanyl-nucleotide exchange factor activity of HPS1:HPS4 [cytosol] HPS1:HPS4 [cytosol] Rab guanyl-nucleotide exchange factor activity (0017112)
Orthologous Events