HGNC Approved Gene Symbol: RAB11A
Cytogenetic location: 15q22.31 Genomic coordinates (GRCh38): 15:65,869,491-65,891,989 (from NCBI)
Small GTP-binding proteins of the RAB family, such as RAB11A, play essential roles in vesicle and granule targeting (Bao et al., 2002).
Using PCR to amplify Ras and Ras-like sequences from carcinoma and T-cell cDNA libraries, Drivas et al. (1991) obtained a cDNA encoding RAB11A, which they termed YL8. RAB11A shares 69% homology with yeast Ypt3. The deduced 651-amino acid protein has many conserved features of Ras and Rab proteins, except that its C terminus lacks the cys-cys found in other Rab family members. Northern blot analysis detected expression in 4 tumor cell lines.
By screening lambda libraries for small GTP-binding proteins, Gromov et al. (1998) identified 2 cDNAs, arising from alternative splicing, that encode RAB11A. Northern blot analysis revealed ubiquitous expression of 1.0- and 2.3-kb RAB11A transcripts, with highest levels in heart and lowest levels in liver. The larger transcript was more abundant in brain and lung, whereas the smaller transcript was more abundant in placenta and heart.
Using RT-PCR, Bao et al. (2002) cloned RAB11A from human platelets. Western blot analysis detected RAB11A at an apparent molecular mass of 26 kD in human platelets and leukemia cell lines. Western blot analysis of rat tissues detected high Rab11a expression in platelets and much lower expression in kidney, liver, heart, lung, and brain. Differential centrifugation of human platelets showed enrichment of RAB11A in the granule/mitochondrion and membrane fractions, with a small amount in the cytosolic fraction.
Bao et al. (2002) noted that mutation of a conserved glutamine (Q70) to leucine within the GTP-binding motif of RAB11A does not inhibit its GTPase activity (Casanova et al., 1999), in contrast to the effect of similar mutations in most small GTPases. Bao et al. (2002) found that mutation of the conserved glutamines in RAB31 (605694) and RAB32 (612906) also had no effect on their GTPase activities, suggesting that these proteins form a subfamily of small GTPases.
Shirane and Nakayama (2006) identified protrudin (ZFYVE27; 610243) as a mammalian protein that promoted neurite formation through interaction with the guanosine diphosphate (GDP)-bound form of Rab11. Phosphorylation of protrudin by extracellular signal-regulated kinase (ERK; 600997) in response to nerve growth factor (NGFB; 162030) promoted protrudin association with Rab11-GDP. Downregulation of protrudin by RNA interference induced membrane extension in all directions and inhibited neurite formation. Thus, Shirane and Nakayama (2006) concluded that protrudin regulates Rab11-dependent membrane recycling to promote the directional membrane trafficking required for neurite formation.
In muscle and fat cells, insulin (INS; 176730) stimulation activates a signaling cascade that causes intracellular vesicles containing glucose transporter-4 (GLUT4, or SLC2A4; 138190) to translocate to and fuse with the plasma membrane. Using mass spectrometry, Larance et al. (2005) identified Rab10 (612672), Rab11, and Rab14 (612673) on Glut4 vesicles from cultured mouse adipocytes. These vesicles also contained the RAB GTPase-activating protein As160 (TBC1D4; 612465), suggesting that the RAB proteins may be AS160 substrates.
In lethal systemic anthrax, proliferating bacilli secrete large quantities of the toxins lethal factor (LF) and edema factor (EF), leading to widespread vascular leakage and shock. Host targets of LF (mitogen-activated protein-kinase kinases) and EF (cAMP-dependent processes) have been implicated in the initial phase of anthrax. In an investigation of toxin action during the final stage of infection, Guichard et al. (2010) used Drosophila melanogaster to identify the Rab11/Sec15 (609672) exocyst, which acts at the last step of endocytic recycling, as a novel target of both EF and LF. EF reduces levels of apically localized Rab11 and indirectly blocks vesicle formation by its binding partner and effector Sec15 (Sec15-GFP), whereas LF acts more directly to reduce Sec15-GFP vesicles. Convergent effects of EF and LF on Rab11/Sec15 inhibited expression of and signaling by the Notch ligand Delta and reduced DE-cadherin levels at adherens junctions. In human endothelial cells, the 2 toxins acted in a conserved fashion to block formation of Sec15 vesicles, inhibit Notch signaling through Delta (DLL4; 605185), and reduce cadherin (CDH1; 192090) expression at adherens junctions. Guichard et al. (2010) suggested that this coordinated disruption of the Rab11/Sec15 exocyst by anthrax toxins may contribute to toxin-dependent barrier disruption and vascular dysfunction during Bacillus anthracis infection.
Crystal Structure
Burke et al. (2014) described crystal structures of PI4KIII-beta (PIK4CB; 602758) bound to the small GTPase RAB11A without and with the RAB11 effector protein FIP3 (300248). The RAB11-PI4KIII-beta interface is distinct compared with structures of RAB complexes and does not involve switch regions used by GTPase effectors. Burke et al. (2014) concluded that their data provided a mechanism for how PI4KIII-beta coordinates RAB11 and its effectors on phosphatidylinositol 4-phosphate-enriched membranes and also provided strategies for the design of specific inhibitors that could potentially target plasmodial PI4KIII-beta to combat malaria.
By radiation hybrid analysis and FISH, Gromov et al. (1998) mapped the RAB11A gene to 15q21.3-q22.31.
Bao, X., Faris, A. E., Jang, E. K., Haslam, R. J. Molecular cloning, bacterial expression and properties of Rab31 and Rab32: new blood platelet Rab proteins. Europ. J. Biochem. 269: 259-271, 2002. [PubMed: 11784320] [Full Text: https://doi.org/10.1046/j.0014-2956.2001.02645.x]
Burke, J. E., Inglis, A. J., Perisic, O., Masson, G. R., McLaughlin, S. H., Rutaganira, F., Shokat, K. M., Williams, R. L. Structures of PI4KIII-beta complexes show simultaneous recruitment of Rab11 and its effectors. Science 344: 1035-1038, 2014. [PubMed: 24876499] [Full Text: https://doi.org/10.1126/science.1253397]
Casanova, J. E., Wang, X., Kumar, R., Bhartur, S. G., Navarre, J., Woodrum, J. E., Altschuler, Y., Ray, G. S., Goldenring, J. R. Association of Rab25 and Rab11a with the apical recycling system of polarized Madin-Darby canine kidney cells. Molec. Biol. Cell 10: 47-61, 1999. [PubMed: 9880326] [Full Text: https://doi.org/10.1091/mbc.10.1.47]
Drivas, G. T., Shih, A., Coutavas, E. E., D'Eustachio, P., Rush, M. G. Identification and characterization of a human homolog of the Schizosaccharomyces pombe ras-like gene YPT-3. Oncogene 6: 3-9, 1991. [PubMed: 1704119]
Gromov, P. S., Celis, J. E., Hansen, C., Tommerup, N., Gromova, I., Madsen, P. Human rab11a : transcription, chromosome mapping and effect on the expression levels of host GTP-binding proteins. FEBS Lett. 429: 359-364, 1998. [PubMed: 9662449] [Full Text: https://doi.org/10.1016/s0014-5793(98)00607-3]
Guichard, A., McGillivray, S. M., Cruz-Moreno, B., van Sorge, N. M., Nizet, V., Bier, E. Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst. Nature 467: 854-858, 2010. [PubMed: 20944747] [Full Text: https://doi.org/10.1038/nature09446]
Larance, M., Ramm, G., Stockli, J., van Dam, E. M., Winata, S., Wasinger, V., Simpson, F., Graham, M., Junutula, J. R., Guilhaus, M., James, D. E. Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. J. Biol. Chem. 280: 37803-37813, 2005. [PubMed: 16154996] [Full Text: https://doi.org/10.1074/jbc.M503897200]
Shirane, M., Nakayama, K. I. Protrudin induces neurite formation by directional membrane trafficking. Science 314: 818-821, 2006. [PubMed: 17082457] [Full Text: https://doi.org/10.1126/science.1134027]