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HGNC Approved Gene Symbol: RABEP1
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:5,282,284-5,386,340 (from NCBI)
The small GTPase RAB5 (179512) is a rate-limiting component in membrane docking or fusion in the early endocytic pathway. The GTP-bound form of RAB5 is the active conformation. Using a yeast 2-hybrid screen, Stenmark et al. (1995) identified HeLa cell cDNAs encoding a protein that interacted with the GTP-bound form of RAB5. The predicted 862-amino acid protein was designated rabaptin-5, a name combining the Greek word 'apto,' meaning 'touch', with RAB5. Both the N- and C-terminal regions of rabaptin-5 are predicted to be mainly alpha-helical and contain heptad repeats characteristic of coiled-coil domains. Western blot analysis of mammalian cell extracts indicated that the 115-kD protein is ubiquitously expressed and is present in a major cytosolic and minor endosome-bound pool.
Stenmark et al. (1995) demonstrated that rabaptin-5 binds directly to RAB5 and preferentially to its GTP-bound form. RAB5 recruits rabaptin-5 to early endosomes in a GTP-dependent manner. Overexpression of rabaptin-5 leads to morphologic alterations of the early endosome compartment similar to those induced by overexpression of RAB5. The authors concluded that rabaptin-5 is an effector of RAB5 that transmits the signal of the active GTP-bound RAB5 conformation to the membrane docking and/or fusion apparatus. They proposed a model in which RAB5-GDP is converted by a membrane-bound GDP/GTP exchange factor into the active GTP-bound conformation. Once activated, GTP-bound RAB5 then recruits rabaptin-5 from the cytosol, thereby positioning rabaptin-5 to exert its function in membrane docking or fusion.
Xiao et al. (1997) reported that tuberin (191092) exhibits substantial GTPase-activating protein activity towards RAB5, and that rabaptin-5 mediates the tuberin association with RAB5.
Using immunodepletion experiments, Horiuchi et al. (1997) found that the RABGEF1 (609700)-RABPT5 complex was essential for both homotypic and heterotypic endosome fusions. Both RABGEF1 and RABPT5 bound RAB5 preferentially in the presence of GTP rather than GDP. RABGEF1 displayed specific GDP/GTP exchange activity on RAB5 upon delivery of RAB5 to the membrane.
Mattera et al. (2003) found that the GGAs (e.g., GGA1; 606004), a family of ARF (see 103180)-dependent clathrin adaptors involved in selection of trans-Golgi network cargo, interacted with the RABGEF1-RABPT5 complex in vitro and in vivo.
Omori et al. (2008) identified elipsa, the zebrafish ortholog of TRAF3IP1 (607380), as a component of intraflagellar transport particles, which are involved in the formation and function of cilia. Elipsa interacted with rabaptin-5, which in turn interacted with Rab8 (RAB8A; 165040), a small GTPase localized to cilia. Omori et al. (2008) concluded that elipsa, rabaptin-5, and Rab8 provide a bridge between the intraflagellar transport particle and protein complexes that assemble at the ciliary membrane.
Endocytosis plays a major role in the deactivation of receptors localized to the plasma membrane. Wang et al. (2009) found that hypoxia, via the VHL (608537)-HIF2A (EPAS1; 603349) signaling pathway, downregulated rabaptin-5 expression, leading to decelerated endocytosis and prolonged activation of ligand-bound EGFR (131550). Primary kidney and breast tumors with strong hypoxic signatures showed significantly lower expression of rabaptin-5 RNA and protein. Wang et al. (2009) identified a conserved hypoxia-responsive element (HRE) in the rabaptin-5 promoter that bound in vitro-translated HIF1A (603348) and HIF2A, leading to displacement of RNA polymerase II and attenuating rabaptin-5 transcription.
The RABEP1 gene maps to chromosome 17p13 (Magnusson et al., 2001).
In a patient with chronic myelomonocytic leukemia (CMML; see 607785) and an acquired t(5;17)(q33;p13), Magnusson et al. (2001) demonstrated rabaptin-5 as a novel partner fused in-frame to the 5-prime portion of the PDGFBR gene (173410). The fusion protein included more than 85% of the native rabaptin-5 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRB. Rabaptin-5 is an essential and rate-limiting component of early endosomal fusion. The RABEP1/PDGFRB fusion protein links 2 important pathways of growth regulation.
Horiuchi, H., Lippe, R., McBride, H. M., Rubino, M., Woodman, P., Stenmark, H., Rybin, V., Wilm, M., Ashman, K., Mann, M., Zerial, M. A novel Rab5 GDP/GTP exchange factor complexed to rabaptin-5 links nucleotide exchange to effector recruitment and function. Cell 90: 1149-1159, 1997. [PubMed: 9323142] [Full Text: https://doi.org/10.1016/s0092-8674(00)80380-3]
Magnusson, M. K., Meade, K. E., Brown, K. E., Arthur, D. C., Krueger, L. A., Barrett, A. J., Dunbar, C. E. Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Blood 98: 2518-2525, 2001. [PubMed: 11588050] [Full Text: https://doi.org/10.1182/blood.v98.8.2518]
Mattera, R., Arighi, C. N., Lodge, R., Zerial, M., Bonifacino, J. S. Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5 complex. EMBO J. 22: 78-88, 2003. [PubMed: 12505986] [Full Text: https://doi.org/10.1093/emboj/cdg015]
Omori, Y., Zhao, C., Saras, A., Mukhopadhyay, S., Kim, W., Furukawa, T., Sengupta, P., Veraksa, A., Malicki, J. elipsa is an early determinant of ciliogenesis that links the IFT particle to membrane-associated small GTPase Rab8. Nature Cell Biol. 10: 437-444, 2008. [PubMed: 18364699] [Full Text: https://doi.org/10.1038/ncb1706]
Stenmark, H., Vitale, G., Ullrich, O., Zerial, M. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell 83: 423-432, 1995. [PubMed: 8521472] [Full Text: https://doi.org/10.1016/0092-8674(95)90120-5]
Wang, Y., Roche, O., Yan, M. S., Finak, G., Evans, A. J., Metcalf, J. L., Hast, B. E., Hanna, S. C., Wondergem, B., Furge, K. A., Irwin, M. S., Kim, W. Y., Teh, B. T., Grinstein, S., Park, M., Marsden, P. A., Ohh, M. Regulation of endocytosis via the oxygen-sensing pathway. Nature Med. 15: 319-324, 2009. [PubMed: 19252501] [Full Text: https://doi.org/10.1038/nm.1922]
Xiao, G.-H., Shoarinejad, F., Jin, F., Golemis, E. A., Yeung, R. S. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J. Biol. Chem. 272: 6097-6100, 1997. [PubMed: 9045618] [Full Text: https://doi.org/10.1074/jbc.272.10.6097]