RALB explained

Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the RALB gene on chromosome 2.^[1] This protein is one of two paralogs of the Ral protein, the other being RalA, and part of the Ras GTPase family.^[2] RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.^{[2] [3] [4]} Its biological role thus implicates it in many cancers.^[4]

Structure

The Ral isoforms share an 80% overall match in amino acid sequence and 100% match in their effector-binding region. The two isoforms mainly differ in the C-terminal hypervariable region, which contains multiple sites for post-translational modification, leading to diverging subcellular localization and biological function. For example, phosphorylation of Serine 194 on RalA by the kinase Aurora A results in the relocation of RalA to the inner mitochondrial membrane, where RalA helps carry out mitochondrial fission; whereas phosphorylation of Serine 198 on RalB by the kinase PKC results in the relocation of RalB to other internal membranes and activation of its tumorigenic function.^[4]

Function

RalB is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases.^[2] As a Ras GTPase, RalB functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalB can be activated by RalGEFs and, in turn, activate effectors in signal transduction pathways leading to biological outcomes.^{[2] [3]} For instance, RalB interacts with two components of the exocyst, Exo84 and Sec5, to promote autophagosome assembly, secretory vesicle trafficking, and tethering. Other downstream biological functions include exocytosis, receptor-mediated endocytosis, tight junction biogenesis, filopodia formation, mitochondrial fission, and cytokinesis.^{[2] [4] [5]}

While the above functions appear to be shared between the two Ral isoforms, their differential subcellular localizations result in their differing involvement in certain biological processes. In particular, RalB is more involved in apoptosis and cell motility.^{[3] [4]} Moreover, RalB specifically interacts with Exo84 to assemble the beclin-1–VPS34 autophagy initiation complex, and with Sec5 to activate the innate immune response via the Tank-binding kinase 1 (TBK1).^[2]

Clinical significance

Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer.^[4] Though the exact mechanisms remain unclear, studies reveal that RalB promotes tumor invasion and metastasis. As a result, inhibition of RalB inhibits further progression of cancer.^[4] In addition, RalB regulates p53 levels in a K-Ras-independent manner during cancer development.^[3] RalB also promotes cell survival during infection by double-stranded DNA viruses by activating TBK1 to carry out an immune response.^{[2] [4]}

Interactions

RalB has been shown to interact with:

• CDC42,^[3]
• EXOC8,^[6]
• RALBP1,^{[6] [7] [8]} and
• Sec5.^{[2] [4]}

Further reading

• Hsieh CL, Swaroop A, Francke U . Chromosomal localization and cDNA sequence of human ralB, a GTP binding protein. . Somat. Cell Mol. Genet. . 16 . 4 . 407–10 . 1990 . 2120779 . 10.1007/BF01232469 . 46005717 .
• Chardin P, Tavitian A . Coding sequences of human ralA and ralB cDNAs . Nucleic Acids Res. . 17 . 11 . 4380 . 1989 . 2662142 . 317954 . 10.1093/nar/17.11.4380 .
• Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH . Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity . J. Biol. Chem. . 270 . 38 . 22473–7 . 1995 . 7673236 . 10.1074/jbc.270.38.22473 . free .
• Jilkina O, Bhullar RP . Generation of antibodies specific for the RalA and RalB GTP-binding proteins and determination of their concentration and distribution in human platelets . Biochim. Biophys. Acta . 1314 . 1–2 . 157–66 . 1997 . 8972729 . 10.1016/s0167-4889(96)00073-0 .
• Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A . Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral . J. Biol. Chem. . 273 . 2 . 814–21 . 1998 . 9422736 . 10.1074/jbc.273.2.814 . free .
• Sugihara K, Asano S, Tanaka K, Iwamatsu A, Okawa K, Ohta Y . The exocyst complex binds the small GTPase RalA to mediate filopodia formation . Nat. Cell Biol. . 4 . 1 . 73–8 . 2002 . 11744922 . 10.1038/ncb720 . 9528945 .
• Clough RR, Sidhu RS, Bhullar RP . Calmodulin binds RalA and RalB and is required for the thrombin-induced activation of Ral in human platelets . J. Biol. Chem. . 277 . 32 . 28972–80 . 2002 . 12034722 . 10.1074/jbc.M201504200 . free .
• Chien Y, White MA . RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival . EMBO Rep. . 4 . 8 . 800–6 . 2004 . 12856001 . 1326339 . 10.1038/sj.embor.embor899 .
• Hernández-Muñoz I, Benet M, Calero M, Jiménez M, Díaz R, Pellicer A . rgr oncogene: activation by elimination of translational controls and mislocalization . Cancer Res. . 63 . 14 . 4188–95 . 2003 . 12874025 .
• Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA . Ral GTPases regulate exocyst assembly through dual subunit interactions . J. Biol. Chem. . 278 . 51 . 51743–8 . 2004 . 14525976 . 10.1074/jbc.M308702200 . free .
• Sidhu RS, Clough RR, Bhullar RP . Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin . J. Biol. Chem. . 280 . 23 . 21933–41 . 2005 . 15817490 . 10.1074/jbc.M412966200 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Chien Y, Kim S, Bumeister R, Loo YM, Kwon SW, Johnson CL, Balakireva MG, Romeo Y, Kopelovich L, Gale M, Yeaman C, Camonis JH, Zhao Y, White MA . RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival . Cell . 127 . 1 . 157–70 . 2006 . 17018283 . 10.1016/j.cell.2006.08.034 . 9878037 . free .
• Lim KH, O'Hayer K, Adam SJ, Kendall SD, Campbell PM, Der CJ, Counter CM . Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells . Curr. Biol. . 16 . 24 . 2385–94 . 2007 . 17174914 . 10.1016/j.cub.2006.10.023 . free .
• Smith SC, Oxford G, Baras AS, Owens C, Havaleshko D, Brautigan DL, Safo MK, Theodorescu D . Expression of ral GTPases, their effectors, and activators in human bladder cancer . Clin. Cancer Res. . 13 . 13 . 3803–13 . 2007 . 17606711 . 10.1158/1078-0432.CCR-06-2419 . free .
• Yin J, Pollock C, Tracy K, Chock M, Martin P, Oberst M, Kelly K . Activation of the RalGEF/Ral Pathway Promotes Prostate Cancer Metastasis to Bone . Mol. Cell. Biol. . 27 . 21 . 7538–50 . 2007 . 17709381 . 2169046 . 10.1128/MCB.00955-07 .

Notes and References

1. Web site: Entrez Gene: RALB v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein).
2. Simicek M, Lievens S, Laga M, Guzenko D, Aushev VN, Kalev P, Baietti MF, Strelkov SV, Gevaert K, Tavernier J, Sablina AA . The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response . Nature Cell Biology . 15 . 10 . 1220–30 . Oct 2013 . 24056301 . 10.1038/ncb2847 . 205287526 .
3. Tecleab A, Zhang X, Sebti SM . Ral GTPase down-regulation stabilizes and reactivates p53 to inhibit malignant transformation . The Journal of Biological Chemistry . 289 . 45 . 31296–309 . Nov 2014 . 25210032 . 10.1074/jbc.M114.565796 . 4223330. free .
4. Kashatus DF . Ral GTPases in tumorigenesis: emerging from the shadows . Experimental Cell Research . 319 . 15 . 2337–42 . Sep 2013 . 23830877 . 10.1016/j.yexcr.2013.06.020 . 4270277.
5. Hazelett CC, Sheff D, Yeaman C . RalA and RalB differentially regulate development of epithelial tight junctions . Molecular Biology of the Cell . 22 . 24 . 4787–800 . Dec 2011 . 22013078 . 10.1091/mbc.E11-07-0657 . 3237622.
6. Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA . Ral GTPases regulate exocyst assembly through dual subunit interactions . J. Biol. Chem. . 278 . 51 . 51743–8 . Dec 2003 . 14525976 . 10.1074/jbc.M308702200 . free .
7. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
8. Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH . Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity . J. Biol. Chem. . 270 . 38 . 22473–7 . Sep 1995 . 7673236 . 10.1074/jbc.270.38.22473. free .