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
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRALB, RAS like proto-oncogene B
External IDsOMIM: 179551 MGI: 1927244 HomoloGene: 20632 GeneCards: RALB
Gene location (Human)
Chr.Chromosome 2 (human)[1]
Band2q14.2Start120,240,064 bp[1]
End120,294,710 bp[1]
RNA expression pattern


More reference expression data
Orthologs
SpeciesHumanMouse
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 MbChr 1: 119.47 – 119.5 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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:

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

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