RALA: Difference between revisions

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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-A (RalA)''' is a [[protein]] that in humans is encoded by the ''RALA'' [[gene]] on chromosome 7.<ref name="pmid3292391">{{cite journal | vauthors = Rousseau-Merck MF, Bernheim A, Chardin P, Miglierina R, Tavitian A, Berger R | title = The ras-related ral gene maps to chromosome 7p15-22 | journal = Human Genetics | volume = 79 | issue = 2 | pages = 132–6 | date = Jun 1988 | pmid = 3292391 | pmc =  | doi = 10.1007/BF00280551 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: RALA v-ral simian leukemia viral oncogene homolog A (ras related)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5898| accessdate = }}</ref> This protein is one of two [[paralog]]s of the Ral protein, the other being [[RALB|RalB]], 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 = PBB_Protein_RALA_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1u8y.
| PDB = {{PDB2|1u8y}}, {{PDB2|1u8z}}, {{PDB2|1u90}}, {{PDB2|1uad}}, {{PDB2|1zc3}}, {{PDB2|1zc4}}, {{PDB2|2a78}}, {{PDB2|2a9k}}, {{PDB2|2bov}}
| Name = V-ral simian leukemia viral oncogene homolog A (ras related)
| HGNCid = 9839
| Symbol = RALA
| AltSymbols =; MGC48949; RAL
| OMIM = 179550
| ECnumber = 
| Homologene = 3942
| MGIid = 1927243
| GeneAtlas_image1 = PBB_GE_RALA_214435_x_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:0006935 |text = chemotaxis}} {{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 = 5898
    | Hs_Ensembl = ENSG00000006451
    | Hs_RefseqProtein = NP_005393
    | Hs_RefseqmRNA = NM_005402
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 7
    | Hs_GenLoc_start = 39629687
    | Hs_GenLoc_end = 39714240
    | Hs_Uniprot = P11233
    | Mm_EntrezGene = 56044
    | Mm_Ensembl = ENSMUSG00000008859
    | Mm_RefseqmRNA = XM_985790
    | Mm_RefseqProtein = XP_990884
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 13
    | Mm_GenLoc_start = 17665717
    | Mm_GenLoc_end = 17729359
    | Mm_Uniprot = Q9CXY0
  }}
}}
'''V-ral simian leukemia viral oncogene homolog A (ras related)''', also known as '''RALA''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: RALA v-ral simian leukemia viral oncogene homolog A (ras related)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5898| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
RalA 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, RalA functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalA 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, RalA interacts with two components of the [[exocyst]], [[EXOC8|Exo84]] and [[Sec5]], to promote [[autophagosome]] assembly, secretory vesicle trafficking, and tethering. Other downstream 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> Ral-mediated exocytosis is also involved such biological processes as [[platelet]] activation, immune cell functions, neuronal [[Synaptic plasticity|plasticity]], and regulation of [[insulin]] action.<ref name=pmid25796063>{{cite journal | vauthors = Shirakawa R, Horiuchi H | title = Ral GTPases: crucial mediators of exocytosis and tumourigenesis | journal = Journal of Biochemistry | volume = 157 | issue = 5 | pages = 285–99 | date = May 2015 | pmid = 25796063 | doi = 10.1093/jb/mvv029 }}</ref>
| section_title =  
| summary_text = The product of this gene belongs to the small GTPase superfamily, Ras family of proteins. GTP-binding proteins mediate the transmembrane signaling initiated by the occupancy of certain cell surface receptors. This gene encodes a low molecular mass ras-like GTP-binding protein that shares about 50% similarity with other ras proteins.<ref name="entrez">{{cite web | title = Entrez Gene: RALA v-ral simian leukemia viral oncogene homolog A (ras related)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5898| 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, RalA is more involved in anchorage-independent cell growth, vesicle trafficking, and cytoskeletal organization.<ref name="pmid25210032"/><ref name="pmid21645515">{{cite journal | vauthors = Jeon H, Zheng LT, Lee S, Lee WH, Park N, Park JY, Heo WD, Lee MS, Suk K | title = Comparative analysis of the role of small G proteins in cell migration and cell death: cytoprotective and promigratory effects of RalA | journal = Experimental Cell Research | volume = 317 | issue = 14 | pages = 2007–18 | date = Aug 2011 | pmid = 21645515 | doi = 10.1016/j.yexcr.2011.05.021 }}</ref> Moreover, RalA specifically interacts with Exo84 and Sec5 to regulate transport of membrane proteins in polarized epithelial cells and [[GLUT4]] to the plasma membrane, as well as mitochondrial fission for cell division.<ref name="pmid24056301"/>
{{reflist|2}}
 
==Further reading==
== Clinical significance ==
{{refbegin | 2}}
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 RalA promotes anchorage-independent growth in cancer cells.<ref name="pmid25210032"/> As a result, inhibition of RalA inhibits cancer initiation.<ref name="pmid23830877"/>
{{PBB_Further_reading
 
| citations =  
Due to its exocytotic role in platelets, immune cells, neurons, and insulin regulation, downregulation of Ral may lead to [[pathological]] conditions such as [[thrombosis]] and [[metabolic syndrome]]. In chronic thromboembolic [[pulmonary hypertension]] patients, Ral GTPases have been observed to be highly active in their platelets.<ref name=pmid25796063/>
*{{cite journal  | author=Kinsella BT, Erdman RA, Maltese WA |title=Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA. |journal=J. Biol. Chem. |volume=266 |issue= 15 |pages= 9786-94 |year= 1991 |pmid= 1903399 |doi= }}
 
*{{cite journal  | author=Polakis PG, Weber RF, Nevins B, ''et al.'' |title=Identification of the ral and rac1 gene products, low molecular mass GTP-binding proteins from human platelets. |journal=J. Biol. Chem. |volume=264 |issue= 28 |pages= 16383-9 |year= 1989 |pmid= 2550440 |doi= }}
== Interactions ==
*{{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=Rousseau-Merck MF, Bernheim A, Chardin P, ''et al.'' |title=The ras-related ral gene maps to chromosome 7p15-22. |journal=Hum. Genet. |volume=79 |issue= 2 |pages= 132-6 |year= 1988 |pmid= 3292391 |doi= }}
RalA has been shown to [[Protein-protein interaction|interact]] with:
*{{cite journal | author=Cantor SB, Urano T, Feig LA |title=Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases. |journal=Mol. Cell. Biol. |volume=15 |issue= 8 |pages= 4578-84 |year= 1995 |pmid= 7623849 |doi= }}
*[[EXOC8]],<ref name="pmid24056301"/>
*{{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= }}
* [[Filamin]],<ref name = pmid10051605>{{cite journal | vauthors = Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP | title = The small GTPase RalA targets filamin to induce filopodia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 5 | pages = 2122–8 | date = Mar 1999 | pmid = 10051605 | pmc = 26747 | doi = 10.1073/pnas.96.5.2122 }}</ref>
*{{cite journal | author=Wang KL, Khan MT, Roufogalis BD |title=Identification and characterization of a calmodulin-binding domain in Ral-A, a Ras-related GTP-binding protein purified from human erythrocyte membrane. |journal=J. Biol. Chem. |volume=272 |issue= 25 |pages= 16002-9 |year= 1997 |pmid= 9188503 |doi= }}
* [[Phospholipase D1|PLD1]],<ref name = pmid9207251>{{cite journal | vauthors = Luo JQ, Liu X, Hammond SM, Colley WC, Feig LA, Frohman MA, Morris AJ, Foster DA | title = RalA interacts directly with the Arf-responsive, PIP2-dependent phospholipase D1 | journal = Biochemical and Biophysical Research Communications | volume = 235 | issue = 3 | pages = 854–9 | date = Jun 1997 | pmid = 9207251 | doi = 10.1006/bbrc.1997.6793 }}</ref><ref name = pmid9688545>{{cite journal | vauthors = Kim JH, Lee SD, Han JM, Lee TG, Kim Y, Park JB, Lambeth JD, Suh PG, Ryu SH | title = Activation of phospholipase D1 by direct interaction with ADP-ribosylation factor 1 and RalA | journal = FEBS Letters | volume = 430 | issue = 3 | pages = 231–5 | date = Jul 1998 | pmid = 9688545 | doi = 10.1016/S0014-5793(98)00661-9 }}</ref>
*{{cite journal | author=Luo JQ, Liu X, Hammond SM, ''et al.'' |title=RalA interacts directly with the Arf-responsive, PIP2-dependent phospholipase D1. |journal=Biochem. Biophys. Res. Commun. |volume=235 |issue= 3 |pages= 854-9 |year= 1997 |pmid= 9207251 |doi= 10.1006/bbrc.1997.6793 }}
*[[Sec5]],<ref name="pmid24056301"/><ref name="pmid23830877"/>  and
*{{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= }}
* [[RALBP1]].<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 = The Journal of Biological Chemistry | volume = 278 | issue = 51 | pages = 51743–8 | date = Dec 2003 | pmid = 14525976 | doi = 10.1074/jbc.M308702200 }}</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 = The Journal of Biological Chemistry | volume = 270 | issue = 38 | pages = 22473–7 | date = Sep 1995 | pmid = 7673236 | doi = 10.1074/jbc.270.38.22473 }}</ref><ref name = pmid7623849>{{cite journal | vauthors = Cantor SB, Urano T, Feig LA | title = Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases | journal = Molecular and Cellular Biology | volume = 15 | issue = 8 | pages = 4578–84 | date = Aug 1995 | pmid = 7623849 | pmc = 230698 | doi = 10.1128/mcb.15.8.4578}}</ref><ref name = pmid9422736>{{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 = The Journal of Biological Chemistry | volume = 273 | issue = 2 | pages = 814–21 | date = Jan 1998 | pmid = 9422736 | doi = 10.1074/jbc.273.2.814 }}</ref>
*{{cite journal  | author=Vavvas D, Li X, Avruch J, Zhang XF |title=Identification of Nore1 as a potential Ras effector. |journal=J. Biol. Chem. |volume=273 |issue= 10 |pages= 5439-42 |year= 1998 |pmid= 9488663 |doi=  }}
 
*{{cite journal | author=Kim JH, Lee SD, Han JM, ''et al.'' |title=Activation of phospholipase D1 by direct interaction with ADP-ribosylation factor 1 and RalA. |journal=FEBS Lett. |volume=430 |issue= 3 |pages= 231-5 |year= 1998 |pmid= 9688545 |doi=  }}
== References ==
*{{cite journal | author=Ohta Y, Suzuki N, Nakamura S, ''et al.'' |title=The small GTPase RalA targets filamin to induce filopodia. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue= 5 |pages= 2122-8 |year= 1999 |pmid= 10051605 |doi= }}
{{reflist|33em}}
*{{cite journal | author=Wang KL, Roufogalis BD |title=Ca2+/calmodulin stimulates GTP binding to the ras-related protein ral-A. |journal=J. Biol. Chem. |volume=274 |issue= 21 |pages= 14525-8 |year= 1999 |pmid= 10329639 |doi=  }}
 
*{{cite journal | author=Suzuki J, Yamazaki Y, Li G, ''et al.'' |title=Involvement of Ras and Ral in chemotactic migration of skeletal myoblasts. |journal=Mol. Cell. Biol. |volume=20 |issue= 13 |pages= 4658-65 |year= 2000 |pmid= 10848592 |doi= }}
== Further reading ==
*{{cite journal | author=de Bruyn KM, de Rooij J, Wolthuis RM, ''et al.'' |title=RalGEF2, a pleckstrin homology domain containing guanine nucleotide exchange factor for Ral. |journal=J. Biol. Chem. |volume=275 |issue= 38 |pages= 29761-6 |year= 2000 |pmid= 10889189 |doi= 10.1074/jbc.M001160200 }}
{{refbegin|33em}}
*{{cite journal | author=Brymora A, Valova VA, Larsen MR, ''et al.'' |title=The brain exocyst complex interacts with RalA in a GTP-dependent manner: identification of a novel mammalian Sec3 gene and a second Sec15 gene. |journal=J. Biol. Chem. |volume=276 |issue= 32 |pages= 29792-7 |year= 2001 |pmid= 11406615 |doi= 10.1074/jbc.C100320200 }}
* {{cite journal | vauthors = Kinsella BT, Erdman RA, Maltese WA | title = Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA | journal = The Journal of Biological Chemistry | volume = 266 | issue = 15 | pages = 9786–94 | date = May 1991 | pmid = 1903399 | 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 | vauthors = Polakis PG, Weber RF, Nevins B, Didsbury JR, Evans T, Snyderman R | title = Identification of the ral and rac1 gene products, low molecular mass GTP-binding proteins from human platelets | journal = The Journal of Biological Chemistry | volume = 264 | issue = 28 | pages = 16383–9 | date = Oct 1989 | pmid = 2550440 | doi =  }}
*{{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 | vauthors = Chardin P, Tavitian A | title = Coding sequences of human ralA and ralB cDNAs | journal = Nucleic Acids Research | volume = 17 | issue = 11 | pages = 4380 | date = Jun 1989 | pmid = 2662142 | pmc = 317954 | doi = 10.1093/nar/17.11.4380 }}
*{{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 | vauthors = Cantor SB, Urano T, Feig LA | title = Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases | journal = Molecular and Cellular Biology | volume = 15 | issue = 8 | pages = 4578–84 | date = Aug 1995 | pmid = 7623849 | pmc = 230698 | doi =  10.1128/mcb.15.8.4578}}
*{{cite journal | author=Xu L, Frankel P, Jackson D, ''et al.'' |title=Elevated phospholipase D activity in H-Ras- but not K-Ras-transformed cells by the synergistic action of RalA and ARF6. |journal=Mol. Cell. Biol. |volume=23 |issue= 2 |pages= 645-54 |year= 2003 |pmid= 12509462 |doi=  }}
* {{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 = The Journal of Biological Chemistry | volume = 270 | issue = 38 | pages = 22473–7 | date = Sep 1995 | pmid = 7673236 | doi = 10.1074/jbc.270.38.22473 }}
}}
* {{cite journal | vauthors = Wang KL, Khan MT, Roufogalis BD | title = Identification and characterization of a calmodulin-binding domain in Ral-A, a Ras-related GTP-binding protein purified from human erythrocyte membrane | journal = The Journal of Biological Chemistry | volume = 272 | issue = 25 | pages = 16002–9 | date = Jun 1997 | pmid = 9188503 | doi = 10.1074/jbc.272.25.16002 }}
* {{cite journal | vauthors = Luo JQ, Liu X, Hammond SM, Colley WC, Feig LA, Frohman MA, Morris AJ, Foster DA | title = RalA interacts directly with the Arf-responsive, PIP2-dependent phospholipase D1 | journal = Biochemical and Biophysical Research Communications | volume = 235 | issue = 3 | pages = 854–9 | date = Jun 1997 | pmid = 9207251 | doi = 10.1006/bbrc.1997.6793 }}
* {{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 = The Journal of Biological Chemistry | volume = 273 | issue = 2 | pages = 814–21 | date = Jan 1998 | pmid = 9422736 | doi = 10.1074/jbc.273.2.814 }}
* {{cite journal | vauthors = Vavvas D, Li X, Avruch J, Zhang XF | title = Identification of Nore1 as a potential Ras effector | journal = The Journal of Biological Chemistry | volume = 273 | issue = 10 | pages = 5439–42 | date = Mar 1998 | pmid = 9488663 | doi = 10.1074/jbc.273.10.5439 }}
* {{cite journal | vauthors = Kim JH, Lee SD, Han JM, Lee TG, Kim Y, Park JB, Lambeth JD, Suh PG, Ryu SH | title = Activation of phospholipase D1 by direct interaction with ADP-ribosylation factor 1 and RalA | journal = FEBS Letters | volume = 430 | issue = 3 | pages = 231–5 | date = Jul 1998 | pmid = 9688545 | doi = 10.1016/S0014-5793(98)00661-9 }}
* {{cite journal | vauthors = Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP | title = The small GTPase RalA targets filamin to induce filopodia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 5 | pages = 2122–8 | date = Mar 1999 | pmid = 10051605 | pmc = 26747 | doi = 10.1073/pnas.96.5.2122 }}
* {{cite journal | vauthors = Wang KL, Roufogalis BD | title = Ca2+/calmodulin stimulates GTP binding to the ras-related protein ral-A | journal = The Journal of Biological Chemistry | volume = 274 | issue = 21 | pages = 14525–8 | date = May 1999 | pmid = 10329639 | doi = 10.1074/jbc.274.21.14525 }}
* {{cite journal | vauthors = Suzuki J, Yamazaki Y, Li G, Kaziro Y, Koide H, Guang L | title = Involvement of Ras and Ral in chemotactic migration of skeletal myoblasts | journal = Molecular and Cellular Biology | volume = 20 | issue = 13 | pages = 4658–65 | date = Jul 2000 | pmid = 10848592 | pmc = 85875 | doi = 10.1128/MCB.20.13.4658-4665.2000 }}
* {{cite journal | vauthors = de Bruyn KM, de Rooij J, Wolthuis RM, Rehmann H, Wesenbeek J, Cool RH, Wittinghofer AH, Bos JL | title = RalGEF2, a pleckstrin homology domain containing guanine nucleotide exchange factor for Ral | journal = The Journal of Biological Chemistry | volume = 275 | issue = 38 | pages = 29761–6 | date = Sep 2000 | pmid = 10889189 | doi = 10.1074/jbc.M001160200 }}
* {{cite journal | vauthors = Brymora A, Valova VA, Larsen MR, Roufogalis BD, Robinson PJ | title = The brain exocyst complex interacts with RalA in a GTP-dependent manner: identification of a novel mammalian Sec3 gene and a second Sec15 gene | journal = The Journal of Biological Chemistry | volume = 276 | issue = 32 | pages = 29792–7 | date = Aug 2001 | pmid = 11406615 | doi = 10.1074/jbc.C100320200 }}
* {{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 = Nature Cell Biology | volume = 4 | issue = 1 | pages = 73–8 | date = Jan 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 = The Journal of Biological Chemistry | volume = 277 | issue = 32 | pages = 28972–80 | date = Aug 2002 | pmid = 12034722 | doi = 10.1074/jbc.M201504200 }}
* {{cite journal | vauthors = Xu L, Frankel P, Jackson D, Rotunda T, Boshans RL, D'Souza-Schorey C, Foster DA | title = Elevated phospholipase D activity in H-Ras- but not K-Ras-transformed cells by the synergistic action of RalA and ARF6 | journal = Molecular and Cellular Biology | volume = 23 | issue = 2 | pages = 645–54 | date = Jan 2003 | pmid = 12509462 | pmc = 151535 | doi = 10.1128/MCB.23.2.645-654.2003 }}
{{refend}}
{{refend}}


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Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7.[1][2] This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family.[3] RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.[3][4][5] Its biological role thus implicates it in many cancers.[5]

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.[5]

Function

RalA is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases.[3] As a Ras GTPase, RalA functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalA can be activated by RalGEFs and, in turn, activate effectors in signal transduction pathways leading to biological outcomes.[3][4] For instance, RalA interacts with two components of the exocyst, Exo84 and Sec5, to promote autophagosome assembly, secretory vesicle trafficking, and tethering. Other downstream functions include exocytosis, receptor-mediated endocytosis, tight junction biogenesis, filopodia formation, mitochondrial fission, and cytokinesis.[3][5][6] Ral-mediated exocytosis is also involved such biological processes as platelet activation, immune cell functions, neuronal plasticity, and regulation of insulin action.[7]

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, RalA is more involved in anchorage-independent cell growth, vesicle trafficking, and cytoskeletal organization.[4][8] Moreover, RalA specifically interacts with Exo84 and Sec5 to regulate transport of membrane proteins in polarized epithelial cells and GLUT4 to the plasma membrane, as well as mitochondrial fission for cell division.[3]

Clinical significance

Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer.[5] Though the exact mechanisms remain unclear, studies reveal that RalA promotes anchorage-independent growth in cancer cells.[4] As a result, inhibition of RalA inhibits cancer initiation.[5]

Due to its exocytotic role in platelets, immune cells, neurons, and insulin regulation, downregulation of Ral may lead to pathological conditions such as thrombosis and metabolic syndrome. In chronic thromboembolic pulmonary hypertension patients, Ral GTPases have been observed to be highly active in their platelets.[7]

Interactions

RalA has been shown to interact with:

References

  1. ↑ Rousseau-Merck MF, Bernheim A, Chardin P, Miglierina R, Tavitian A, Berger R (Jun 1988). "The ras-related ral gene maps to chromosome 7p15-22". Human Genetics. 79 (2): 132–6. doi:10.1007/BF00280551. PMID 3292391.
  2. ↑ "Entrez Gene: RALA v-ral simian leukemia viral oncogene homolog A (ras related)".
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 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.
  4. ↑ 4.0 4.1 4.2 4.3 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.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 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.
  6. ↑ 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.
  7. ↑ 7.0 7.1 Shirakawa R, Horiuchi H (May 2015). "Ral GTPases: crucial mediators of exocytosis and tumourigenesis". Journal of Biochemistry. 157 (5): 285–99. doi:10.1093/jb/mvv029. PMID 25796063.
  8. ↑ Jeon H, Zheng LT, Lee S, Lee WH, Park N, Park JY, Heo WD, Lee MS, Suk K (Aug 2011). "Comparative analysis of the role of small G proteins in cell migration and cell death: cytoprotective and promigratory effects of RalA". Experimental Cell Research. 317 (14): 2007–18. doi:10.1016/j.yexcr.2011.05.021. PMID 21645515.
  9. ↑ Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP (Mar 1999). "The small GTPase RalA targets filamin to induce filopodia". Proceedings of the National Academy of Sciences of the United States of America. 96 (5): 2122–8. doi:10.1073/pnas.96.5.2122. PMC 26747. PMID 10051605.
  10. ↑ Luo JQ, Liu X, Hammond SM, Colley WC, Feig LA, Frohman MA, Morris AJ, Foster DA (Jun 1997). "RalA interacts directly with the Arf-responsive, PIP2-dependent phospholipase D1". Biochemical and Biophysical Research Communications. 235 (3): 854–9. doi:10.1006/bbrc.1997.6793. PMID 9207251.
  11. ↑ Kim JH, Lee SD, Han JM, Lee TG, Kim Y, Park JB, Lambeth JD, Suh PG, Ryu SH (Jul 1998). "Activation of phospholipase D1 by direct interaction with ADP-ribosylation factor 1 and RalA". FEBS Letters. 430 (3): 231–5. doi:10.1016/S0014-5793(98)00661-9. PMID 9688545.
  12. ↑ 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". The Journal of Biological Chemistry. 278 (51): 51743–8. doi:10.1074/jbc.M308702200. PMID 14525976.
  13. ↑ 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". The Journal of Biological Chemistry. 270 (38): 22473–7. doi:10.1074/jbc.270.38.22473. PMID 7673236.
  14. ↑ Cantor SB, Urano T, Feig LA (Aug 1995). "Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases". Molecular and Cellular Biology. 15 (8): 4578–84. doi:10.1128/mcb.15.8.4578. PMC 230698. PMID 7623849.
  15. ↑ Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A (Jan 1998). "Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral". The Journal of Biological Chemistry. 273 (2): 814–21. doi:10.1074/jbc.273.2.814. PMID 9422736.

Further reading

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