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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Ras-related protein Ral-B''' ('''RalB''') is a [[protein]] that in humans is encoded by the ''RALB'' [[gene]] on chromosome 2.<ref name="entrez">{{Cite web| title = Entrez Gene: RALB v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5899| accessdate = }}</ref>  This protein is one of two [[paralog]]s of the Ral protein, the other being [[RALA|RalA]], and part of the [[Ras family|Ras]] [[GTPase]] family.<ref name="pmid24056301">{{cite journal | vauthors = Simicek M, Lievens S, Laga M, Guzenko D, Aushev VN, Kalev P, Baietti MF, Strelkov SV, Gevaert K, Tavernier J, Sablina AA | title = The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response | journal = Nature Cell Biology | volume = 15 | issue = 10 | pages = 1220–30 | date = Oct 2013 | pmid = 24056301 | doi = 10.1038/ncb2847 }}</ref> RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.<ref name="pmid24056301"/><ref name="pmid25210032">{{cite journal | vauthors = Tecleab A, Zhang X, Sebti SM | title = Ral GTPase down-regulation stabilizes and reactivates p53 to inhibit malignant transformation | journal = The Journal of Biological Chemistry | volume = 289 | issue = 45 | pages = 31296–309 | date = Nov 2014 | pmid = 25210032 | doi = 10.1074/jbc.M114.565796 | pmc=4223330}}</ref><ref name="pmid23830877">{{cite journal | vauthors = Kashatus DF | title = Ral GTPases in tumorigenesis: emerging from the shadows | journal = Experimental Cell Research | volume = 319 | issue = 15 | pages = 2337–42 | date = Sep 2013 | pmid = 23830877 | doi = 10.1016/j.yexcr.2013.06.020 | pmc=4270277}}</ref> Its biological role thus implicates it in many [[cancer]]s.<ref name="pmid23830877"/>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
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 [[Protein kinase C|PKC]] results in the relocation of RalB to other internal membranes and activation of its tumorigenic function.<ref name="pmid23830877"/>
| image =
| image_source =
| PDB =  
| Name = V-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)
| HGNCid = 9840
| Symbol = RALB
| AltSymbols =;
| OMIM = 179551
| ECnumber = 
| Homologene = 20632
| MGIid = 1927244
| GeneAtlas_image1 = PBB_GE_RALB_202100_at_tn.png
| GeneAtlas_image2 = PBB_GE_RALB_202101_s_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005525 |text = GTP binding}}
| Component = {{GNF_GO|id=GO:0005622 |text = intracellular}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007264 |text = small GTPase mediated signal transduction}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5899
    | Hs_Ensembl = ENSG00000144118
    | Hs_RefseqProtein = NP_002872
    | Hs_RefseqmRNA = NM_002881
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 2
    | Hs_GenLoc_start = 120726884
    | Hs_GenLoc_end = 120768753
    | Hs_Uniprot = P11234
    | Mm_EntrezGene = 64143
    | Mm_Ensembl = ENSMUSG00000004451
    | Mm_RefseqmRNA = NM_022327
    | Mm_RefseqProtein = NP_071722
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 1
    | Mm_GenLoc_start = 121297858
    | Mm_GenLoc_end = 121332182
    | Mm_Uniprot = Q8CCG5
  }}
}}
'''V-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)''', also known as '''RALB''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: RALB v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5899| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
RalB is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases.<ref name="pmid24056301"/> 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.<ref name="pmid24056301"/><ref name="pmid25210032"/> For instance, RalB interacts with two components of the [[exocyst]], [[EXOC8|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]].<ref name="pmid24056301"/><ref name="pmid23830877"/><ref name="pmid22013078">{{cite journal | vauthors = Hazelett CC, Sheff D, Yeaman C | title = RalA and RalB differentially regulate development of epithelial tight junctions | journal = Molecular Biology of the Cell | volume = 22 | issue = 24 | pages = 4787–800 | date = Dec 2011 | pmid = 22013078 | doi = 10.1091/mbc.E11-07-0657 | pmc=3237622}}</ref>
| section_title =  
| summary_text = This gene encodes a GTP-binding protein that belongs to the small GTPase superfamily and Ras family of proteins. GTP-binding proteins mediate the transmembrane signaling initiated by the occupancy of certain cell surface receptors.<ref name="entrez">{{cite web | title = Entrez Gene: RALB v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5899| accessdate = }}</ref>
}}


==References==
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.<ref name="pmid25210032"/><ref name="pmid23830877"/> 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 ([[TANK-binding kinase 1|TBK1]]).<ref name="pmid24056301"/>
{{reflist|2}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Hsieh CL, Swaroop A, Francke U |title=Chromosomal localization and cDNA sequence of human ralB, a GTP binding protein. |journal=Somat. Cell Mol. Genet. |volume=16 |issue= 4 |pages= 407-10 |year= 1990 |pmid= 2120779 |doi=  }}
*{{cite journal  | author=Chardin P, Tavitian A |title=Coding sequences of human ralA and ralB cDNAs. |journal=Nucleic Acids Res. |volume=17 |issue= 11 |pages= 4380 |year= 1989 |pmid= 2662142 |doi=  }}
*{{cite journal  | author=Jullien-Flores V, Dorseuil O, Romero F, ''et al.'' |title=Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. |journal=J. Biol. Chem. |volume=270 |issue= 38 |pages= 22473-7 |year= 1995 |pmid= 7673236 |doi=  }}
*{{cite journal  | author=Jilkina O, Bhullar RP |title=Generation of antibodies specific for the RalA and RalB GTP-binding proteins and determination of their concentration and distribution in human platelets. |journal=Biochim. Biophys. Acta |volume=1314 |issue= 1-2 |pages= 157-66 |year= 1997 |pmid= 8972729 |doi=  }}
*{{cite journal  | author=Ikeda M, Ishida O, Hinoi T, ''et al.'' |title=Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral. |journal=J. Biol. Chem. |volume=273 |issue= 2 |pages= 814-21 |year= 1998 |pmid= 9422736 |doi=  }}
*{{cite journal  | author=Sugihara K, Asano S, Tanaka K, ''et al.'' |title=The exocyst complex binds the small GTPase RalA to mediate filopodia formation. |journal=Nat. Cell Biol. |volume=4 |issue= 1 |pages= 73-8 |year= 2002 |pmid= 11744922 |doi= 10.1038/ncb720 }}
*{{cite journal  | author=Clough RR, Sidhu RS, Bhullar RP |title=Calmodulin binds RalA and RalB and is required for the thrombin-induced activation of Ral in human platelets. |journal=J. Biol. Chem. |volume=277 |issue= 32 |pages= 28972-80 |year= 2002 |pmid= 12034722 |doi= 10.1074/jbc.M201504200 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  | author=Chien Y, White MA |title=RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. |journal=EMBO Rep. |volume=4 |issue= 8 |pages= 800-6 |year= 2004 |pmid= 12856001 |doi= 10.1038/sj.embor.embor899 }}
*{{cite journal  | author=Hernández-Muñoz I, Benet M, Calero M, ''et al.'' |title=rgr oncogene: activation by elimination of translational controls and mislocalization. |journal=Cancer Res. |volume=63 |issue= 14 |pages= 4188-95 |year= 2003 |pmid= 12874025 |doi=  }}
*{{cite journal  | author=Moskalenko S, Tong C, Rosse C, ''et al.'' |title=Ral GTPases regulate exocyst assembly through dual subunit interactions. |journal=J. Biol. Chem. |volume=278 |issue= 51 |pages= 51743-8 |year= 2004 |pmid= 14525976 |doi= 10.1074/jbc.M308702200 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Sidhu RS, Clough RR, Bhullar RP |title=Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin. |journal=J. Biol. Chem. |volume=280 |issue= 23 |pages= 21933-41 |year= 2005 |pmid= 15817490 |doi= 10.1074/jbc.M412966200 }}
*{{cite journal  | author=Rual JF, Venkatesan K, Hao T, ''et al.'' |title=Towards a proteome-scale map of the human protein-protein interaction network. |journal=Nature |volume=437 |issue= 7062 |pages= 1173-8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209 }}
*{{cite journal  | author=Chien Y, Kim S, Bumeister R, ''et al.'' |title=RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. |journal=Cell |volume=127 |issue= 1 |pages= 157-70 |year= 2006 |pmid= 17018283 |doi= 10.1016/j.cell.2006.08.034 }}
*{{cite journal  | author=Lim KH, O'Hayer K, Adam SJ, ''et al.'' |title=Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. |journal=Curr. Biol. |volume=16 |issue= 24 |pages= 2385-94 |year= 2007 |pmid= 17174914 |doi= 10.1016/j.cub.2006.10.023 }}
*{{cite journal  | author=Smith SC, Oxford G, Baras AS, ''et al.'' |title=Expression of ral GTPases, their effectors, and activators in human bladder cancer. |journal=Clin. Cancer Res. |volume=13 |issue= 13 |pages= 3803-13 |year= 2007 |pmid= 17606711 |doi= 10.1158/1078-0432.CCR-06-2419 }}
*{{cite journal  | author=Yin J, Pollock C, Tracy K, ''et al.'' |title=Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. |journal=Mol. Cell. Biol. |volume=27 |issue= 21 |pages= 7538-50 |year= 2007 |pmid= 17709381 |doi= 10.1128/MCB.00955-07 }}
}}
{{refend}}


{{protein-stub}}
== Clinical significance ==
{{WikiDoc Sources}}
Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer.<ref name="pmid23830877"/> 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.<ref name="pmid23830877"/> In addition, RalB regulates p53 levels in a K-Ras-independent manner during cancer development.<ref name="pmid25210032"/> RalB also promotes cell survival during infection by double-stranded DNA viruses by activating TBK1 to carry out an immune response.<ref name="pmid24056301"/><ref name="pmid23830877"/>
 
== Interactions ==
 
RalB has been shown to [[Protein-protein interaction|interact]] with:
* [[CDC42]],<ref name="pmid25210032"/>
* [[EXOC8]],<ref name = pmid14525976>{{cite journal | vauthors = Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA | title = Ral GTPases regulate exocyst assembly through dual subunit interactions | journal = J. Biol. Chem. | volume = 278 | issue = 51 | pages = 51743–8 | date = Dec 2003 | pmid = 14525976 | doi = 10.1074/jbc.M308702200 }}</ref>
* [[RALBP1]],<ref name = pmid14525976/><ref name = pmid16189514>{{cite journal | vauthors = 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 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}</ref><ref name = pmid7673236>{{cite journal | vauthors = Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH | title = Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity | journal = J. Biol. Chem. | volume = 270 | issue = 38 | pages = 22473–7 | date = Sep 1995 | pmid = 7673236 | doi =  10.1074/jbc.270.38.22473}}</ref> and
* [[Sec5]].<ref name="pmid24056301"/><ref name="pmid23830877"/>
{{Clear}}
 
== References ==
{{Reflist|33em}}
 
== Further reading ==
{{Refbegin|33em}}
* {{cite journal | vauthors = Hsieh CL, Swaroop A, Francke U | title = Chromosomal localization and cDNA sequence of human ralB, a GTP binding protein. | journal = Somat. Cell Mol. Genet. | volume = 16 | issue = 4 | pages = 407–10 | year = 1990 | pmid = 2120779 | doi = 10.1007/BF01232469 }}
* {{cite journal | vauthors = Chardin P, Tavitian A | title = Coding sequences of human ralA and ralB cDNAs | journal = Nucleic Acids Res. | volume = 17 | issue = 11 | pages = 4380 | year = 1989 | pmid = 2662142 | pmc = 317954 | doi = 10.1093/nar/17.11.4380 }}
* {{cite journal | vauthors = Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH | title = Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity | journal = J. Biol. Chem. | volume = 270 | issue = 38 | pages = 22473–7 | year = 1995 | pmid = 7673236 | doi = 10.1074/jbc.270.38.22473 }}
* {{cite journal | vauthors = Jilkina O, Bhullar RP | title = Generation of antibodies specific for the RalA and RalB GTP-binding proteins and determination of their concentration and distribution in human platelets | journal = Biochim. Biophys. Acta | volume = 1314 | issue = 1–2 | pages = 157–66 | year = 1997 | pmid = 8972729 | doi = 10.1016/s0167-4889(96)00073-0 }}
* {{cite journal | vauthors = Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A | title = Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral | journal = J. Biol. Chem. | volume = 273 | issue = 2 | pages = 814–21 | year = 1998 | pmid = 9422736 | doi = 10.1074/jbc.273.2.814 }}
* {{cite journal | vauthors = Sugihara K, Asano S, Tanaka K, Iwamatsu A, Okawa K, Ohta Y | title = The exocyst complex binds the small GTPase RalA to mediate filopodia formation | journal = Nat. Cell Biol. | volume = 4 | issue = 1 | pages = 73–8 | year = 2002 | pmid = 11744922 | doi = 10.1038/ncb720 }}
* {{cite journal | vauthors = Clough RR, Sidhu RS, Bhullar RP | title = Calmodulin binds RalA and RalB and is required for the thrombin-induced activation of Ral in human platelets | journal = J. Biol. Chem. | volume = 277 | issue = 32 | pages = 28972–80 | year = 2002 | pmid = 12034722 | doi = 10.1074/jbc.M201504200 }}
* {{cite journal | vauthors = Chien Y, White MA | title = RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival | journal = EMBO Rep. | volume = 4 | issue = 8 | pages = 800–6 | year = 2004 | pmid = 12856001 | pmc = 1326339 | doi = 10.1038/sj.embor.embor899 }}
* {{cite journal | vauthors = Hernández-Muñoz I, Benet M, Calero M, Jiménez M, Díaz R, Pellicer A | title = rgr oncogene: activation by elimination of translational controls and mislocalization | journal = Cancer Res. | volume = 63 | issue = 14 | pages = 4188–95 | year = 2003 | pmid = 12874025 | doi =  }}
* {{cite journal | vauthors = Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA | title = Ral GTPases regulate exocyst assembly through dual subunit interactions | journal = J. Biol. Chem. | volume = 278 | issue = 51 | pages = 51743–8 | year = 2004 | pmid = 14525976 | doi = 10.1074/jbc.M308702200 }}
* {{cite journal | vauthors = Sidhu RS, Clough RR, Bhullar RP | title = Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin | journal = J. Biol. Chem. | volume = 280 | issue = 23 | pages = 21933–41 | year = 2005 | pmid = 15817490 | doi = 10.1074/jbc.M412966200 }}
* {{cite journal | vauthors = 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 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | year = 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}
* {{cite journal | vauthors = 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 | title = RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival | journal = Cell | volume = 127 | issue = 1 | pages = 157–70 | year = 2006 | pmid = 17018283 | doi = 10.1016/j.cell.2006.08.034 }}
* {{cite journal | vauthors = Lim KH, O'Hayer K, Adam SJ, Kendall SD, Campbell PM, Der CJ, Counter CM | title = Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells | journal = Curr. Biol. | volume = 16 | issue = 24 | pages = 2385–94 | year = 2007 | pmid = 17174914 | doi = 10.1016/j.cub.2006.10.023 }}
* {{cite journal | vauthors = Smith SC, Oxford G, Baras AS, Owens C, Havaleshko D, Brautigan DL, Safo MK, Theodorescu D | title = Expression of ral GTPases, their effectors, and activators in human bladder cancer | journal = Clin. Cancer Res. | volume = 13 | issue = 13 | pages = 3803–13 | year = 2007 | pmid = 17606711 | doi = 10.1158/1078-0432.CCR-06-2419 }}
* {{cite journal | vauthors = Yin J, Pollock C, Tracy K, Chock M, Martin P, Oberst M, Kelly K | title = Activation of the RalGEF/Ral Pathway Promotes Prostate Cancer Metastasis to Bone | journal = Mol. Cell. Biol. | volume = 27 | issue = 21 | pages = 7538–50 | year = 2007 | pmid = 17709381 | pmc = 2169046 | doi = 10.1128/MCB.00955-07 }}
{{Refend}}
 
{{Portal|Mitochondria}}

Latest revision as of 08:52, 10 September 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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:

References

  1. ↑ "Entrez Gene: RALB v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)".
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 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.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 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.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 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.
  5. ↑ 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.
  6. ↑ 6.0 6.1 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.
  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 (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.
  8. ↑ 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.
  • 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.
  • 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.
  • 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.
  • 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.
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