RALB

Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the RALB gene on chromosome 2.[5] This protein is one of two paralogs of the Ral protein, the other being RalA, and part of the Ras GTPase family.[6] RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.[6][7][8] Its biological role thus implicates it in many cancers.[8]

RALB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KE5, 2KWI
Identifiers
Aliases	RALB, RAS like proto-oncogene B
External IDs	OMIM: 179551 MGI: 1927244 HomoloGene: 20632 GeneCards: RALB
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q14.2 Start 120,240,064 bp[1] End 120,294,710 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1|1 E2.3 Start 119,470,305 bp[2] End 119,504,794 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • GDP binding • ATPase binding • GTP binding • GO:0001948 protein binding • GTPase activity • ubiquitin protein ligase binding Cellular component • membrane • cell membrane • autophagosome • exocyst • extracellular exosome • intracellular • midbody Biological process • positive regulation of protein phosphorylation • positive regulation of autophagosome assembly • cellular response to starvation • negative regulation of protein binding • positive regulation of protein serine/threonine kinase activity • cell division • regulation of exocyst assembly • cellular response to exogenous dsRNA • cell cycle • positive regulation of protein binding • signal transduction • regulation of exocyst localization • apoptotic process • Ras protein signal transduction Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5899	64143
Ensembl	ENSG00000144118	ENSMUSG00000004451
UniProt	P11234	Q9JIW9
RefSeq (mRNA)	NM_002881 NM_001369400	NM_022327
RefSeq (protein)	NP_002872 NP_001356329	NP_071722
Location (UCSC)	Chr 2: 120.24 – 120.29 Mb	Chr 1: 119.47 – 119.5 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[8]

Function

RalB is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases.[6] 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.[6][7] 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.[6][8][9]

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.[7][8] 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).[6]

Clinical significance

Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer.[8] 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.[8] In addition, RalB regulates p53 levels in a K-Ras-independent manner during cancer development.[7] RalB also promotes cell survival during infection by double-stranded DNA viruses by activating TBK1 to carry out an immune response.[6][8]

Interactions

RalB has been shown to interact with:

• CDC42,[7]
• EXOC8,[10]
• RALBP1,[10][11][12] and
• Sec5.[6][8]

References

1. GRCh38: Ensembl release 89: ENSG00000144118 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000004451 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: RALB v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)".
6. Simicek M, Lievens S, Laga M, Guzenko D, Aushev VN, Kalev P, Baietti MF, Strelkov SV, Gevaert K, Tavernier J, Sablina AA (Oct 2013). "The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response". Nature Cell Biology. 15 (10): 1220–30. doi:10.1038/ncb2847. PMID 24056301. S2CID 205287526.
7. Tecleab A, Zhang X, Sebti SM (Nov 2014). "Ral GTPase down-regulation stabilizes and reactivates p53 to inhibit malignant transformation". The Journal of Biological Chemistry. 289 (45): 31296–309. doi:10.1074/jbc.M114.565796. PMC 4223330. PMID 25210032.
8. Kashatus DF (Sep 2013). "Ral GTPases in tumorigenesis: emerging from the shadows". Experimental Cell Research. 319 (15): 2337–42. doi:10.1016/j.yexcr.2013.06.020. PMC 4270277. PMID 23830877.
9. Hazelett CC, Sheff D, Yeaman C (Dec 2011). "RalA and RalB differentially regulate development of epithelial tight junctions". Molecular Biology of the Cell. 22 (24): 4787–800. doi:10.1091/mbc.E11-07-0657. PMC 3237622. PMID 22013078.
10. Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA (Dec 2003). "Ral GTPases regulate exocyst assembly through dual subunit interactions". J. Biol. Chem. 278 (51): 51743–8. doi:10.1074/jbc.M308702200. PMID 14525976.
11. 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 (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
12. Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH (Sep 1995). "Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity". J. Biol. Chem. 270 (38): 22473–7. doi:10.1074/jbc.270.38.22473. PMID 7673236.

Further reading

• Hsieh CL, Swaroop A, Francke U (1990). "Chromosomal localization and cDNA sequence of human ralB, a GTP binding protein". Somat. Cell Mol. Genet. 16 (4): 407–10. doi:10.1007/BF01232469. PMID 2120779. S2CID 46005717.
• Chardin P, Tavitian A (1989). "Coding sequences of human ralA and ralB cDNAs". Nucleic Acids Res. 17 (11): 4380. doi:10.1093/nar/17.11.4380. PMC 317954. PMID 2662142.
• Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH (1995). "Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity". J. Biol. Chem. 270 (38): 22473–7. doi:10.1074/jbc.270.38.22473. PMID 7673236.
• Jilkina O, Bhullar RP (1997). "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. doi:10.1016/s0167-4889(96)00073-0. PMID 8972729.
• Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A (1998). "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. doi:10.1074/jbc.273.2.814. PMID 9422736.
• Sugihara K, Asano S, Tanaka K, Iwamatsu A, Okawa K, Ohta Y (2002). "The exocyst complex binds the small GTPase RalA to mediate filopodia formation". Nat. Cell Biol. 4 (1): 73–8. doi:10.1038/ncb720. PMID 11744922. S2CID 9528945.
• Clough RR, Sidhu RS, Bhullar RP (2002). "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. doi:10.1074/jbc.M201504200. PMID 12034722.
• Chien Y, White MA (2004). "RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival". EMBO Rep. 4 (8): 800–6. doi:10.1038/sj.embor.embor899. PMC 1326339. PMID 12856001.
• Hernández-Muñoz I, Benet M, Calero M, Jiménez M, Díaz R, Pellicer A (2003). "rgr oncogene: activation by elimination of translational controls and mislocalization". Cancer Res. 63 (14): 4188–95. PMID 12874025.
• Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA (2004). "Ral GTPases regulate exocyst assembly through dual subunit interactions". J. Biol. Chem. 278 (51): 51743–8. doi:10.1074/jbc.M308702200. PMID 14525976.
• Sidhu RS, Clough RR, Bhullar RP (2005). "Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin". J. Biol. Chem. 280 (23): 21933–41. doi:10.1074/jbc.M412966200. PMID 15817490.
• 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 (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514. S2CID 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 (2006). "RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival". Cell. 127 (1): 157–70. doi:10.1016/j.cell.2006.08.034. PMID 17018283. S2CID 9878037.
• Lim KH, O'Hayer K, Adam SJ, Kendall SD, Campbell PM, Der CJ, Counter CM (2007). "Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells". Curr. Biol. 16 (24): 2385–94. doi:10.1016/j.cub.2006.10.023. PMID 17174914.
• Smith SC, Oxford G, Baras AS, Owens C, Havaleshko D, Brautigan DL, Safo MK, Theodorescu D (2007). "Expression of ral GTPases, their effectors, and activators in human bladder cancer". Clin. Cancer Res. 13 (13): 3803–13. doi:10.1158/1078-0432.CCR-06-2419. PMID 17606711.
• Yin J, Pollock C, Tracy K, Chock M, Martin P, Oberst M, Kelly K (2007). "Activation of the RalGEF/Ral Pathway Promotes Prostate Cancer Metastasis to Bone". Mol. Cell. Biol. 27 (21): 7538–50. doi:10.1128/MCB.00955-07. PMC 2169046. PMID 17709381.