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Gene Review

RAB4A  -  RAB4A, member RAS oncogene family

Homo sapiens

Synonyms: HRES-1, HRES-1/RAB4, HRES1, RAB4, Ras-related protein Rab-4A
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Disease relevance of RAB4A

  • In order to evaluate the role of Rab proteins in ENaC function, Rab4 wild-type (WT), the GTPase-deficient mutant Rab4Q67L, and the dominant negative GDP-locked mutant Rab4S22N were over-expressed in the colon cancer cell line, HT-29 and amiloride-sensitive currents were recorded [1].
  • After global ischemia there was a marked increase in immunoreactivity of both endocytic markers, rabaptin-5 and rab4, in neurons, and to a lesser extent in glia compared to controls [2].
  • Human rab4 and rab5 were expressed in chicken embryo fibroblasts using a Sindbis virus expression vector [3].
  • Stimulation by HIV-1 of HRES-1/Rab4 expression and its regulation of CD4 recycling reveal novel coordinate interactions between an infectious retrovirus and the human genome [4].
  • Regulation of CD4 Expression via Recycling by HRES-1/RAB4 Controls Susceptibility to HIV Infection [4].

High impact information on RAB4A

  • Wild-type rab4 caused a redistribution of Tfn-R's from endosomes to the plasma membrane [5].
  • To determine its role during endocytosis, we generated stable cell lines that overexpressed mutant or wild-type rab4 [5].
  • We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of Rab1Ap and Rab4p [6].
  • We also show that the distribution of Rab1Ap and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells [6].
  • In particular, detailed descriptions have emerged of the mechanisms that recruit integrins and growth factor receptors to Rab4- and Rab11-driven pathways [7].

Biological context of RAB4A


Anatomical context of RAB4A


Associations of RAB4A with chemical compounds

  • These data suggest that abnormal membrane recycling in NPFs results from specific inhibition of rab4 function by excess cholesterol in EEs [14].
  • Mutation of Ser196 to glutamine or aspartic acid completely prevented rab4 phosphorylation in mitotic cells and also blocked its appearance in the cytosol [13].
  • Taken together, our data provide evidence that Rabip4s, possibly via their interaction with Rab4, regulate integrin trafficking and are involved in the migration of NIH 3T3 fibroblasts [15].
  • We propose that the subcellular localization of the protein is primarily driven by the RUN domain to endosomal microdomains characterized by Triton X-100 insolubility and that the FYVE domain and the Rab4-binding domain then allow for the recruitment of the protein to lipophilic microdomains enriched in phosphatidylinositol 3-phosphate [16].
  • Furthermore, association of Rab4 with the latex bead-containing phagosomes was revealed by flow cytometry [17].

Physical interactions of RAB4A


Enzymatic interactions of RAB4A

  • We found a pronounced increase of the Rab4 soluble form and its soluble complexes with the tyrosine-phosphorylated GDI-2 [22].

Co-localisations of RAB4A

  • We recently demonstrated that epitope-tagged Rab15 (HArab15) co-localizes with Rab4, -5, and -11 on early endosomal membranes in CHO cells (Zuk, P. A., and Elferink, L. A. (1999) J. Biol. Chem. 274, 22303-22312) [23].

Regulatory relationships of RAB4A

  • CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl [9].

Other interactions of RAB4A

  • We investigated the role of the rab4 effector rabaptin-5alpha and its putative partner gamma(1)-adaptin in membrane recycling [12].
  • We have identified a novel 80-kDa protein that interacts specifically with the GTP-bound conformation of Rab4, and subsequent work has shown that it also interacts strongly with Rab11 [24].
  • Differentiation of MEG-01 cells induced by 100 nM 12-O-tetradecanoylphorbol-13-acetate revealed the considerable increases in mRNA expression of rap1B, rab3B, rab4, ram and ran whereas the levels of rap2B, rhoA and rac1 decreased [25].
  • We propose that CD2AP/CMS, through interactions with Rab4 and c-Cbl, controls early endosome morphology and may play a role in traffic between early and late endosomes, and thus in the degradative pathway [9].
  • To address the mechanisms that regulate communication between such domains, we searched for proteins that interact with both Rab5 and Rab4 [18].

Analytical, diagnostic and therapeutic context of RAB4A

  • Active status of Rab4 was confirmed by GTP overlay assay, while its expression was verified by Western blotting [11].
  • Confocal immunofluorescence microscopy showed that the early endosomal GTPases Rab4 and Rab5 both do not codistribute with Rab7 within the same cell [26].
  • Peptide mapping of Rab4 was performed to take advantage of additional scissile bonds within Switch II to determine more precisely the limits of the nucleotide-dependent protease-accessible region [27].
  • Confocal and electron microscopic immunocytochemistry revealed that rab4 colocalized with the actin terminal web and microvilli in the apical region of the exocrine acinar cells [28].
  • Following high-speed centrifugation of postnuclear supernatants prepared from 1-day neonatal pancreatic homogenates, rab4 partitioned into a Triton X-100 insoluble particulate fraction and was partially solubilized upon extraction with 0.1 M Na2CO3, pH 11.5, or 1 M KCl, suggesting that rab4 was not an integral membrane protein [28].


  1. Rab4 GTP/GDP modulates amiloride-sensitive sodium channel (ENaC) function in colonic epithelia. Saxena, S.K., Singh, M., Shibata, H., Kaur, S., George, C. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  2. Endocytic pathway alterations in human hippocampus after global ischemia and the influence of APOE genotype. McColl, B.W., Graham, D.I., Weir, C.J., White, F., Horsburgh, K. Am. J. Pathol. (2003) [Pubmed]
  3. Post-translational processing and membrane association of the two early endosome-associated rab GTP-binding proteins (rab4 and rab5). Li, G., Stahl, P.D. Arch. Biochem. Biophys. (1993) [Pubmed]
  4. Regulation of CD4 Expression via Recycling by HRES-1/RAB4 Controls Susceptibility to HIV Infection. Nagy, G., Ward, J., Mosser, D.D., Koncz, A., Gergely, P., Stancato, C., Qian, Y., Fernandez, D., Niland, B., Grossman, C.E., Telarico, T., Banki, K., Perl, A. J. Biol. Chem. (2006) [Pubmed]
  5. The small GTP-binding protein rab4 controls an early sorting event on the endocytic pathway. van der Sluijs, P., Hull, M., Webster, P., Mâle, P., Goud, B., Mellman, I. Cell (1992) [Pubmed]
  6. Phosphorylation of two small GTP-binding proteins of the Rab family by p34cdc2. Bailly, E., McCaffrey, M., Touchot, N., Zahraoui, A., Goud, B., Bornens, M. Nature (1991) [Pubmed]
  7. Endocytic recycling pathways: emerging regulators of cell migration. Jones, M.C., Caswell, P.T., Norman, J.C. Curr. Opin. Cell Biol. (2006) [Pubmed]
  8. The RCP-Rab11 complex regulates endocytic protein sorting. Peden, A.A., Schonteich, E., Chun, J., Junutula, J.R., Scheller, R.H., Prekeris, R. Mol. Biol. Cell (2004) [Pubmed]
  9. CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl. Cormont, M., Metón, I., Mari, M., Monzo, P., Keslair, F., Gaskin, C., McGraw, T.E., Le Marchand-Brustel, Y. Traffic (2003) [Pubmed]
  10. High resolution crystal structures of human Rab4a in its active and inactive conformations. Huber, S.K., Scheidig, A.J. FEBS Lett. (2005) [Pubmed]
  11. Rab4GTPase modulates CFTR function by impairing channel expression at plasma membrane. Saxena, S.K., Kaur, S., George, C. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  12. 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]
  13. Reversible phosphorylation--dephosphorylation determines the localization of rab4 during the cell cycle. van der Sluijs, P., Hull, M., Huber, L.A., Mâle, P., Goud, B., Mellman, I. EMBO J. (1992) [Pubmed]
  14. Elevated endosomal cholesterol levels in Niemann-Pick cells inhibit rab4 and perturb membrane recycling. Choudhury, A., Sharma, D.K., Marks, D.L., Pagano, R.E. Mol. Biol. Cell (2004) [Pubmed]
  15. The Rab4A Effector Protein Rabip4 Is Involved in Migration of NIH 3T3 Fibroblasts. Vukmirica, J., Monzo, P., Le Marchand-Brustel, Y., Cormont, M. J. Biol. Chem. (2006) [Pubmed]
  16. Role of the FYVE finger and the RUN domain for the subcellular localization of Rabip4. Mari, M., Macia, E., Le Marchand-Brustel, Y., Cormont, M. J. Biol. Chem. (2001) [Pubmed]
  17. Neisseria gonorrhoeae porin modulates phagosome maturation. Mosleh, I.M., Huber, L.A., Steinlein, P., Pasquali, C., Günther, D., Meyer, T.F. J. Biol. Chem. (1998) [Pubmed]
  18. Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes. de Renzis, S., Sönnichsen, B., Zerial, M. Nat. Cell Biol. (2002) [Pubmed]
  19. Distinct Rab-binding domains mediate the interaction of Rabaptin-5 with GTP-bound Rab4 and Rab5. Vitale, G., Rybin, V., Christoforidis, S., Thornqvist, P., McCaffrey, M., Stenmark, H., Zerial, M. EMBO J. (1998) [Pubmed]
  20. Characterisation of the Rab binding properties of Rab coupling protein (RCP) by site-directed mutagenesis. Lindsay, A.J., McCaffrey, M.W. FEBS Lett. (2004) [Pubmed]
  21. Accumulation of rab4GTP in the cytoplasm and association with the peptidyl-prolyl isomerase pin1 during mitosis. Gerez, L., Mohrmann, K., van Raak, M., Jongeneelen, M., Zhou, X.Z., Lu, K.P., van Der Sluijs, P. Mol. Biol. Cell (2000) [Pubmed]
  22. General role of GDP dissociation inhibitor 2 in membrane release of Rab proteins: modulations of its functional interactions by in vitro and in vivo structural modifications. Shisheva, A., Chinni, S.R., DeMarco, C. Biochemistry (1999) [Pubmed]
  23. Rab15 differentially regulates early endocytic trafficking. Zuk, P.A., Elferink, L.A. J. Biol. Chem. (2000) [Pubmed]
  24. Rab coupling protein (RCP), a novel Rab4 and Rab11 effector protein. Lindsay, A.J., Hendrick, A.G., Cantalupo, G., Senic-Matuglia, F., Goud, B., Bucci, C., McCaffrey, M.W. J. Biol. Chem. (2002) [Pubmed]
  25. Differential expression of low Mr GTP-binding proteins in human megakaryoblastic leukemia cell line, MEG-01, and their possible involvement in the differentiation process. Nagata, K., Okano, Y., Nozawa, Y. Thromb. Haemost. (1997) [Pubmed]
  26. Rab4 and Rab7 define distinct nonoverlapping endosomal compartments. Bottger, G., Nagelkerken, B., van der Sluijs, P. J. Biol. Chem. (1996) [Pubmed]
  27. Conformationally variable Rab protein surface regions mapped by limited proteolysis and homology modelling. Nikolova, L., Soman, K., Nichols, J.C., Daniel, D.S., Dickey, B.F., Hoffenberg, S. Biochem. J. (1998) [Pubmed]
  28. Rab4 associates with the actin terminal web in developing rat pancreatic acinar cells. Valentijn, J.A., LaCivita, D.Q., Gumkowski, F.D., Jamieson, J.D. Eur. J. Cell Biol. (1997) [Pubmed]
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