RALA

Last updated
RALA
Protein RALA PDB 1u8y.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases RALA , RAL, RALA Ras like proto-oncogene A, RAS like proto-oncogene A, HINCONS
External IDs OMIM: 179550 MGI: 1927243 HomoloGene: 3942 GeneCards: RALA
Orthologs
SpeciesHumanMouse
Entrez

5898

56044

Ensembl

ENSG00000006451

ENSMUSG00000008859

UniProt

P11233

P63321

RefSeq (mRNA)

NM_005402

NM_019491

RefSeq (protein)

NP_005393

NP_062364

Location (UCSC) Chr 7: 39.62 – 39.71 Mb Chr 13: 18.06 – 18.12 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7. [5] [6] This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family. [7] RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. [7] [8] [9] Its biological role thus implicates it in many cancers. [9]

Contents

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. [9]

Function

RalA is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases. [7] 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. [7] [8] 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. [7] [9] [10] Ral-mediated exocytosis is also involved such biological processes as platelet activation, immune cell functions, neuronal plasticity, and regulation of insulin action. [11]

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. [8] [12] 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. [7]

Clinical significance

Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer. [9] Though the exact mechanisms remain unclear, studies reveal that RalA promotes anchorage-independent growth in cancer cells. [8] As a result, inhibition of RalA inhibits cancer initiation. [9]

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. [11]

Interactions

RalA has been shown to interact with:

Related Research Articles

GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a protein domain common to many GTPases.

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog is a protein that in humans is encoded by the Cdc42 gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

<span class="mw-page-title-main">RHOB</span> Protein-coding gene in the species Homo sapiens

Ras homolog gene family, member B, also known as RHOB, is a protein which in humans is encoded by the RHOB gene.

<span class="mw-page-title-main">Transforming protein RhoA</span> Protein and coding gene in humans

Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.

<span class="mw-page-title-main">ARF1</span> Protein-coding gene in the species Homo sapiens

ADP-ribosylation factor 1 is a protein that in humans is encoded by the ARF1 gene.

<span class="mw-page-title-main">Phospholipase D1</span> Protein-coding gene in the species Homo sapiens

Phospholipase D1 (PLD1) is an enzyme that in humans is encoded by the PLD1 gene, though analogues are found in plants, fungi, prokaryotes, and even viruses.

<span class="mw-page-title-main">RAP1A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-1A is a protein that in humans is encoded by the RAP1A gene.

<span class="mw-page-title-main">RAB5A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-5A is a protein that in humans is encoded by the RAB5A gene.

<span class="mw-page-title-main">RAP1GAP</span> Protein-coding gene in the species Homo sapiens

Rap1 GTPase-activating protein 1 is an enzyme that in humans is encoded by the RAP1GAP gene.

<span class="mw-page-title-main">RAB11A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-11A is a protein that in humans is encoded by the RAB11A gene.

<span class="mw-page-title-main">RAB4A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-4A is a protein that in humans is encoded by the RAB4A gene.

<span class="mw-page-title-main">RHEB</span> Protein-coding gene in the species Homo sapiens

RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle.

<span class="mw-page-title-main">RAC3</span> Mammalian protein found in Homo sapiens

Ras-related C3 botulinum toxin substrate 3 (Rac3) is a G protein that in humans is encoded by the RAC3 gene. It is an important component of intracellular signalling pathways. Rac3 is a member of the Rac subfamily of the Rho family of small G proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.

<span class="mw-page-title-main">RALBP1</span> Protein-coding gene in the species Homo sapiens

RalA-binding protein 1 is a protein that in humans is encoded by the RALBP1 gene.

<span class="mw-page-title-main">RAP2A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-2a is a protein that in humans is encoded by the RAP2A gene. RAP2A is a member of the Ras-related protein family.

<span class="mw-page-title-main">RAB8A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-8A is a protein that in humans is encoded by the RAB8A gene.

<span class="mw-page-title-main">RhoG</span> Protein-coding gene in the species Homo sapiens

RhoG is a small monomeric GTP-binding protein, and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG.

<span class="mw-page-title-main">RALB</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">TRIM23</span> Protein-coding gene in the species Homo sapiens

GTP-binding protein ARD-1 is a protein that in humans is encoded by the TRIM23 gene.

<span class="mw-page-title-main">Alan Hall</span> British cell biologist and professor

Alan Hall FRS was a British cell biologist and a biology professor at the Sloan-Kettering Institute, where he was chair of the Cell Biology program. Hall was elected a Fellow of the Royal Society in 1999.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000006451 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000008859 - 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. ↑ 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. S2CID   24522661.
  6. ↑ "Entrez Gene: RALA v-ral simian leukemia viral oncogene homolog A (ras related)".
  7. 1 2 3 4 5 6 7 8 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.
  8. 1 2 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.
  9. 1 2 3 4 5 6 7 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.
  10. ↑ 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.
  11. 1 2 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.
  12. ↑ 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.
  13. ↑ 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. Bibcode:1999PNAS...96.2122O. doi: 10.1073/pnas.96.5.2122 . PMC   26747 . PMID   10051605.
  14. ↑ 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.
  15. ↑ 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. S2CID   36075513.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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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