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Gene Review

RAB5A  -  RAB5A, member RAS oncogene family

Homo sapiens

Synonyms: RAB5, Ras-related protein Rab-5A
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Disease relevance of RAB5A


High impact information on RAB5A

  • Here, we report that Rabex-5, a guanine nucleotide exchange factor for Rab5, binds to Ub through two independent UBDs [5].
  • We found a kinesin-3, KIF16B, that transports early endosomes to the plus end of microtubules in a process regulated by the small GTPase Rab5 and its effector, the phosphatidylinositol-3-OH kinase hVPS34 [6].
  • APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment [7].
  • This pathway operates via APPL1 and APPL2, two Rab5 effectors, which reside on a subpopulation of endosomes [7].
  • Our findings identify an endosomal compartment bearing Rab5 and APPL proteins as an intermediate in signaling between the plasma membrane and the nucleus [7].

Chemical compound and disease context of RAB5A

  • The D136N mutant of Rab5, which was predicted to switch specificity from guanine to xanthine nucleotides, was expressed in E. coli, extracted with urea, purified by column chromatography, and refolded by stepwise dialysis against buffer containing XDP [8].

Biological context of RAB5A


Anatomical context of RAB5A

  • TBC1D3 is a member of the TBC1 domain family of proteins that stimulates the intrinsic GTPase activity of RAB5A, an essential actor in early endosome trafficking [13].
  • Microfilament bundles in RAB5A gene over-expressed AGZY83-a cells were shown to be denser than in control cells using confocal laser scanning microscope (CLSM) [1].
  • Rab5 regulates endocytic membrane traffic by specifically recruiting cytosolic effector proteins to their site of action on early endosomal membranes [14].
  • RIN3 expressed in HeLa cells localized to cytoplasmic vesicles and the RIN3-positive vesicles contained Rab5 but not the early endosomal marker EEA1 [15].
  • Staphylococci-containing phagosomes were matured by sequential and dynamic interactions with Rab5- and Rab7-positive vesicles [16].

Associations of RAB5A with chemical compounds

  • We propose that Rab5-dependent formation of membrane domains enriched in phosphatidylinositol-3-phosphate has evolved as a mechanism for the recruitment of multiple effector proteins to mammalian early endosomes, and that these domains are multifunctional, depending on the differing activities of the effector proteins recruited [14].
  • Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor [17].
  • Agonist-induced endocytosis of lysophosphatidic acid-coupled LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent pathway [18].
  • Immune complexes of native tuberin, as well as recombinant protein, possessed activity to stimulate GTP hydrolysis of Rab5 [19].
  • This was dependent on the presence of active forms of Rab5 and the generation of PtdIns 3-P-enriched platforms on early endosomess [20].

Physical interactions of RAB5A


Enzymatic interactions of RAB5A

  • An increase in beta-cleaved soluble APP relative to alpha-cleaved soluble APP was also observed following Rab5 overexpression [24].

Co-localisations of RAB5A

  • Confocal immunofluorescence microscopy of transfected HEp2 cells revealed that the C-terminal part (residues 1277-1411) of EEA1 colocalizes extensively with a GTPase-deficient mutant of the early endosomal GTPase Rab5, while deletion of the FYVE finger or mutations that interfere with zinc binding cause a cytosolic localization [25].

Regulatory relationships of RAB5A

  • Endocytosis of epidermal growth factor receptor regulated by Grb2-mediated recruitment of the Rab5 GTPase-activating protein RN-tre [10].
  • In addition, both dynamin2 K44A and Rab5 S34N mildly inhibited LPA1-dependent activation of serum response factor [18].
  • We conclude that wortmannin alters intracellular trafficking of EGFR by activating Rab5 rather than by inhibiting PI3K [26].
  • RIN1 is also shown to stimulate Rab5 guanine nucleotide exchange, Rab5A-dependent endosome fusion, and EGF receptor-mediated endocytosis [27].
  • The mutant full-length EEA1 caused the accumulation of endosome clusters and suppressed the enlargement of endosomes caused by a persistently active form of Rab5 (Rab5Q79L) [28].

Other interactions of RAB5A

  • The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5 [29].
  • Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain [14].
  • Here, we demonstrate that Grb2 also signals to Rab5, a small GTPase that plays a key role in early endocytic trafficking [10].
  • It has been reported that phosphatidylinositol 3-kinases and FYVE domain proteins, such as EEA1, can be recruited onto early endosomes and act as Rab5 effectors [11].
  • These results indicate that RIN3 biochemically characterized as the stimulator and stabilizer for GTP-Rab5 plays an important role in the transport pathway from plasma membrane to early endosomes [15].

Analytical, diagnostic and therapeutic context of RAB5A


  1. The effect of RAB5A gene on rearrangement of microfilaments in human lung adenocarcinoma cells. Shi, Z.C., Yu, Y., Li, Y., Fu, S.B. Yi Chuan Xue Bao (2005) [Pubmed]
  2. Differential expression of RAB5A in human lung adenocarcinoma cells with different metastasis potential. Yu, L., Hui-chen, F., Chen, Y., Zou, R., Yan, S., Chun-xiang, L., Wu-ru, W., Li, P. Clin. Exp. Metastasis (1999) [Pubmed]
  3. Over-expression of the RAB5 gene in human lung adenocarcinoma cells with high metastatic potential. Li, Y., Meng, X., Feng, H., Zhang, G., Liu, C., Li, P. Chin. Med. Sci. J. (1999) [Pubmed]
  4. PU.1 Redirects Adenovirus to Lysosomes in Alveolar Macrophages, Uncoupling Internalization from Infection. Carey, B., Staudt, M.K., Bonaminio, D., van der Loo, J.C., Trapnell, B.C. J. Immunol. (2007) [Pubmed]
  5. Crystal structure of the ubiquitin binding domains of rabex-5 reveals two modes of interaction with ubiquitin. Penengo, L., Mapelli, M., Murachelli, A.G., Confalonieri, S., Magri, L., Musacchio, A., Di Fiore, P.P., Polo, S., Schneider, T.R. Cell (2006) [Pubmed]
  6. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Hoepfner, S., Severin, F., Cabezas, A., Habermann, B., Runge, A., Gillooly, D., Stenmark, H., Zerial, M. Cell (2005) [Pubmed]
  7. APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Miaczynska, M., Christoforidis, S., Giner, A., Shevchenko, A., Uttenweiler-Joseph, S., Habermann, B., Wilm, M., Parton, R.G., Zerial, M. Cell (2004) [Pubmed]
  8. Functional and structural interactions of the Rab5 D136N mutant with xanthine nucleotides. Hoffenberg, S., Nikolova, L., Pan, J.Y., Daniel, D.S., Wessling-Resnick, M., Knoll, B.J., Dickey, B.F. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  9. Rabaptin-5alpha/rabaptin-4 serves as a linker between rab4 and gamma(1)-adaptin in membrane recycling from endosomes. Deneka, M., Neeft, M., Popa, I., van Oort, M., Sprong, H., Oorschot, V., Klumperman, J., Schu, P., van der Sluijs, P. EMBO J. (2003) [Pubmed]
  10. Endocytosis of epidermal growth factor receptor regulated by Grb2-mediated recruitment of the Rab5 GTPase-activating protein RN-tre. Martinu, L., Santiago-Walker, A., Qi, H., Chou, M.M. J. Biol. Chem. (2002) [Pubmed]
  11. SARA, a FYVE domain protein, affects Rab5-mediated endocytosis. Hu, Y., Chuang, J.Z., Xu, K., McGraw, T.G., Sung, C.H. J. Cell. Sci. (2002) [Pubmed]
  12. PRC17, a novel oncogene encoding a Rab GTPase-activating protein, is amplified in prostate cancer. Pei, L., Peng, Y., Yang, Y., Ling, X.B., Van Eyndhoven, W.G., Nguyen, K.C., Rubin, M., Hoey, T., Powers, S., Li, J. Cancer Res. (2002) [Pubmed]
  13. TBC1D3, a hominoid oncoprotein, is encoded by a cluster of paralogues located on chromosome 17q12. Hodzic, D., Kong, C., Wainszelbaum, M.J., Charron, A.J., Su, X., Stahl, P.D. Genomics (2006) [Pubmed]
  14. Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain. Nielsen, E., Christoforidis, S., Uttenweiler-Joseph, S., Miaczynska, M., Dewitte, F., Wilm, M., Hoflack, B., Zerial, M. J. Cell Biol. (2000) [Pubmed]
  15. RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway. Kajiho, H., Saito, K., Tsujita, K., Kontani, K., Araki, Y., Kurosu, H., Katada, T. J. Cell. Sci. (2003) [Pubmed]
  16. Live cell imaging of phagosome maturation in Staphylococcus aureus infected human endothelial cells: small colony variants are able to survive in lysosomes. Schr??der, A., Kland, R., Peschel, A., von Eiff, C., Aepfelbacher, M. Med. Microbiol. Immunol. (Berl.) (2006) [Pubmed]
  17. Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. Topp, J.D., Gray, N.W., Gerard, R.D., Horazdovsky, B.F. J. Biol. Chem. (2004) [Pubmed]
  18. Agonist-induced endocytosis of lysophosphatidic acid-coupled LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent pathway. Murph, M.M., Scaccia, L.A., Volpicelli, L.A., Radhakrishna, H. J. Cell. Sci. (2003) [Pubmed]
  19. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. Xiao, G.H., Shoarinejad, F., Jin, F., Golemis, E.A., Yeung, R.S. J. Biol. Chem. (1997) [Pubmed]
  20. Localized PtdIns 3,5-P2 synthesis to regulate early endosome dynamics and fusion. Ikonomov, O.C., Sbrissa, D., Shisheva, A. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  21. Determinants of Rab5 interaction with the N terminus of early endosome antigen 1. Merithew, E., Stone, C., Eathiraj, S., Lambright, D.G. J. Biol. Chem. (2003) [Pubmed]
  22. Rab15 effector protein: a novel protein for receptor recycling from the endocytic recycling compartment. Strick, D.J., Elferink, L.A. Mol. Biol. Cell (2005) [Pubmed]
  23. Structure of the APPL1 BAR-PH domain and characterization of its interaction with Rab5. Zhu, G., Chen, J., Liu, J., Brunzelle, J.S., Huang, B., Wakeham, N., Terzyan, S., Li, X., Rao, Z., Li, G., Zhang, X.C. EMBO J. (2007) [Pubmed]
  24. Rab5-stimulated up-regulation of the endocytic pathway increases intracellular beta-cleaved amyloid precursor protein carboxyl-terminal fragment levels and Abeta production. Grbovic, O.M., Mathews, P.M., Jiang, Y., Schmidt, S.D., Dinakar, R., Summers-Terio, N.B., Ceresa, B.P., Nixon, R.A., Cataldo, A.M. J. Biol. Chem. (2003) [Pubmed]
  25. Endosomal localization of the autoantigen EEA1 is mediated by a zinc-binding FYVE finger. Stenmark, H., Aasland, R., Toh, B.H., D'Arrigo, A. J. Biol. Chem. (1996) [Pubmed]
  26. Regulation of epidermal growth factor receptor endocytosis by wortmannin through activation of Rab5 rather than inhibition of phosphatidylinositol 3-kinase. Chen, X., Wang, Z. EMBO Rep. (2001) [Pubmed]
  27. Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1. Tall, G.G., Barbieri, M.A., Stahl, P.D., Horazdovsky, B.F. Dev. Cell (2001) [Pubmed]
  28. Sequential roles for phosphatidylinositol 3-phosphate and Rab5 in tethering and fusion of early endosomes via their interaction with EEA1. Lawe, D.C., Chawla, A., Merithew, E., Dumas, J., Carrington, W., Fogarty, K., Lifshitz, L., Tuft, R., Lambright, D., Corvera, S. J. Biol. Chem. (2002) [Pubmed]
  29. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Lanzetti, L., Rybin, V., Malabarba, M.G., Christoforidis, S., Scita, G., Zerial, M., Di Fiore, P.P. Nature (2000) [Pubmed]
  30. Endosomal trafficking of the Menkes copper ATPase ATP7A is mediated by vesicles containing the Rab7 and Rab5 GTPase proteins. Pascale, M.C., Franceschelli, S., Moltedo, O., Belleudi, F., Torrisi, M.R., Bucci, C., La Fontaine, S., Mercer, J.F., Leone, A. Exp. Cell Res. (2003) [Pubmed]
  31. Distinct structural elements of rab5 define its functional specificity. Stenmark, H., Valencia, A., Martinez, O., Ullrich, O., Goud, B., Zerial, M. EMBO J. (1994) [Pubmed]
  32. Molecular cloning of Rab5 (ApRab5) in Aiptasia pulchella and its retention in phagosomes harboring live zooxanthellae. Chen, M.C., Cheng, Y.M., Hong, M.C., Fang, L.S. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  33. Measurement of the interaction of the p85alpha subunit of phosphatidylinositol 3-kinase with Rab5. Dean Chamberlain, M., Anderson, D.H. Meth. Enzymol. (2005) [Pubmed]
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