Alternative titles; symbols
HGNC Approved Gene Symbol: RAB6A
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:73,675,638-73,761,074 (from NCBI)
The mammalian RAB proteins show striking similarities to the S. cerevisiae YPT1 and SEC4 proteins, Ras-related GTP-binding proteins involved in the regulation of secretion. Zahraoui et al. (1989) isolated cDNAs encoding RAB6 and several other human RAB proteins. The predicted human RAB6 protein contains 208 amino acids. Northern blot analysis revealed that the RAB6 gene was expressed as a 3.6-kb mRNA in a human fibroblast cell line.
By screening a human kidney cDNA library with a DNA fragment of RAB6C (612909), Shan et al. (2000) isolated a RAB6A variant that they called RAB6C. The deduced 208-amino acid protein encoded by this variant differs at only 3 amino acids compared with the previously reported RAB6A isoform.
Using quantitative RT-PCR, Shan et al. (2000) showed that a RAB6A variant that they called RAB6C was downregulated in a multidrug-resistant clone of MCF7 breast cancer cells compared with the parental MCF7 cell line. Reexpression of the RAB6A variant in the resistant cell line restored sensitivity to several anticancer drugs. Flow cytometry experiments showed that sensitivity to doxorubicin was associated with increased drug accumulation in cells expressing the RAB6A variant.
Using a large-scale small interfering RNA screen to identify host factors required by human immunodeficiency virus (HIV)-1 (see 609423), Brass et al. (2008) identified more than 250 HIV-dependency factors (HDFs), 79 of which showed significantly higher expression in immune tissues compared with other tissues. The HDFs RAB6 and VPS53 (615850), retrograde Golgi transport proteins, were involved in viral entry. Brass et al. (2008) proposed that targeting of HDFs essential for the viral cycle but not critical for the host may avoid drug resistance due to viral diversity and escape mutation.
Using protein pull-down assays, Schlager et al. (2010) found that mouse Bicdr1 (BICDL1; 617002) showed strongest interaction with Rab6b (615852), followed by Rab6a, with little binding to other Rabs tested. In a yeast 2-hybrid assay, the C-terminal region of Bicdr1 encompassing the second coiled-coil domain bound to constitutively active, GTPase-deficient Rab6a, but not to inactive, GDP-locked Rab6a. Overexpression of Bicdr1 in human and monkey epithelial cells caused accumulation of Bicdr1 in the pericentrosomal region along with Rab6-positive vesicles. In early cultures of mouse hippocampal neurons, Bicdr1 accumulated Rab6- and Npy (162640)-positive secretory vesicles around the centrosome in a dose-dependent manner, restricted anterograde secretory transport, and inhibited neurite outgrowth. Schlager et al. (2010) concluded that RAB6 and BICDR1 function in retrograde transport of secretory vesicles.
Pusapati et al. (2012) found that human RGP1 (615742) and RIC1 (610354) interacted independently with GDP-bound RAB6A, but neither functioned alone as a guanine nucleotide exchange factor (GEF) for RAB6A. In contrast, coexpression of RIC1 and RGP1 resulted in a RIC1-RGP1 complex that showed concentration-dependent GEF activity for RAB6A, but not other RAB proteins tested. Loss of RIC1 or RGP1 from human cell lines destabilized RAB6A protein and decreased its abundance at the Golgi complex, concomitant with a block in RAB6A-dependent retrograde transport of mannose 6-phosphate receptor (IGF2R; 147280) from late endosomes to the Golgi.
By in situ hybridization, Rousseau-Merck et al. (1991) assigned the RAB6 gene to chromosome 2q14-q21.
Hartz (2016) mapped the RAB6A gene to chromosome 11q13.4 based on an alignment of the RAB6A sequence (GenBank AF119836) with the genomic sequence (GRCh38).
Brass, A. L., Dykxhoorn, D. M., Benita, Y., Yan, N., Engelman, A., Xavier, R. J., Lieberman, J., Elledge, S. J. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319: 921-926, 2008. [PubMed: 18187620] [Full Text: https://doi.org/10.1126/science.1152725]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/5/2016.
Pusapati, G. V., Luchetti, G., Pfeffer, S. R. Ric1-Rgp1 complex is a guanine nucleotide exchange factor for the late Golgi Rab6A GTPase and an effector of the medial Golgi Rab33B GTPase. J. Biol. Chem. 287: 42129-42137, 2012. [PubMed: 23091056] [Full Text: https://doi.org/10.1074/jbc.M112.414565]
Rousseau-Merck, M.-F., Zahraoui, A., Touchot, N., Tavitian, A., Berger, R. Chromosome assignment of four RAS-related RAB genes. Hum. Genet. 86: 350-354, 1991. [PubMed: 1999336] [Full Text: https://doi.org/10.1007/BF00201831]
Schlager, M. A., Kapitein, L. C., Grigoriev, I., Burzynski, G. M., Wulf, P. S., Kiejzer, N., de Graaff, E., Fukuda, M., Shepherd, I. T., Akhmanova, A., Hoogenraad, C. C. Pericentrosomal targeting of Rab6 secretory vesicles by Bicaudal-D-related protein 1 (BICDR-1) regulates neuritogenesis. EMBO J. 29: 1637-1651, 2010. [PubMed: 20360680] [Full Text: https://doi.org/10.1038/emboj.2010.51]
Shan, J., Mason, J. M., Yuan, L., Barcia, M., Porti, D., Calabro, A., Budman, D., Vinciguerra, V., Xu, H. Rab6c, a new member of the Rab gene family, is involved in drug resistance in MCF7/AdrR cells. Gene 257: 67-75, 2000. [PubMed: 11054569] [Full Text: https://doi.org/10.1016/s0378-1119(00)00395-4]
Zahraoui, A., Touchot, N., Chardin, P., Tavitian, A. The human rab genes encode a family of GTP-binding proteins related to yeast YPT1 and SEC4 products involved in secretion. J. Biol. Chem. 264: 12394-12401, 1989. [PubMed: 2501306]