RALA
{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7.{{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 | doi = 10.1007/BF00280551 | s2cid = 24522661 }}{{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}} This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family.{{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 | s2cid = 205287526 }} RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.{{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| doi-access = free }}{{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}} Its biological role thus implicates it in many cancers.
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.
Function
RalA is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases. 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. 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.{{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}} Ral-mediated exocytosis is also involved such biological processes as platelet activation, immune cell functions, neuronal plasticity, and regulation of insulin action.{{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 | doi-access = free }}
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.{{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 }} 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.
Clinical significance
Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer. Though the exact mechanisms remain unclear, studies reveal that RalA promotes anchorage-independent growth in cancer cells. As a result, inhibition of RalA inhibits cancer initiation.
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.
Interactions
RalA has been shown to interact with:
- EXOC8,
- Filamin,{{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 | bibcode = 1999PNAS...96.2122O | doi-access = free }}
- PLD1,{{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 | doi-access = free }}{{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 | s2cid = 36075513 | doi-access = free }}
- Sec5, and
- RALBP1.{{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 | doi-access = free }}{{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 | doi-access = free }}{{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 | 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 | doi-access = free }}
References
{{reflist|33em}}
Further reading
{{refbegin|33em}}
- {{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 | doi = 10.1016/S0021-9258(18)92889-9 | pmid = 1903399 | doi-access = free }}
- {{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 | doi = 10.1016/S0021-9258(19)84717-8 | pmid = 2550440 | doi-access = free }}
- {{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 | 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 | 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 | doi-access = free }}
- {{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 | doi-access = free }}
- {{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 | doi-access = free }}
- {{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 | doi-access = free }}
- {{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 | doi-access = free }}
- {{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 | s2cid = 36075513 | doi-access = free }}
- {{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 | bibcode = 1999PNAS...96.2122O | doi-access = free }}
- {{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 | doi-access = free }}
- {{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 | doi-access = free }}
- {{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 | doi-access = free }}
- {{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 | s2cid = 9528945 }}
- {{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 | doi-access = free }}
- {{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}}
External links
- {{PDBe-KB2|P11233|Ras-related protein Ral-A}}
{{PDB Gallery|geneid=5898}}