Biology:RALA

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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. ↑ "The ras-related ral gene maps to chromosome 7p15-22". Human Genetics 79 (2): 132–6. Jun 1988. doi:10.1007/BF00280551. PMID 3292391. 
  2. ↑ "Entrez Gene: RALA v-ral simian leukemia viral oncogene homolog A (ras related)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5898. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 "The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response". Nature Cell Biology 15 (10): 1220–30. Oct 2013. doi:10.1038/ncb2847. PMID 24056301. 
  4. ↑ 4.0 4.1 4.2 4.3 "Ral GTPase down-regulation stabilizes and reactivates p53 to inhibit malignant transformation". The Journal of Biological Chemistry 289 (45): 31296–309. Nov 2014. doi:10.1074/jbc.M114.565796. PMID 25210032. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Ral GTPases in tumorigenesis: emerging from the shadows". Experimental Cell Research 319 (15): 2337–42. Sep 2013. doi:10.1016/j.yexcr.2013.06.020. PMID 23830877. 
  6. ↑ "RalA and RalB differentially regulate development of epithelial tight junctions". Molecular Biology of the Cell 22 (24): 4787–800. Dec 2011. doi:10.1091/mbc.E11-07-0657. PMID 22013078. 
  7. ↑ 7.0 7.1 "Ral GTPases: crucial mediators of exocytosis and tumourigenesis". Journal of Biochemistry 157 (5): 285–99. May 2015. doi:10.1093/jb/mvv029. PMID 25796063. 
  8. ↑ "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. Aug 2011. doi:10.1016/j.yexcr.2011.05.021. PMID 21645515. 
  9. ↑ "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. Mar 1999. doi:10.1073/pnas.96.5.2122. PMID 10051605. Bibcode: 1999PNAS...96.2122O. 
  10. ↑ "RalA interacts directly with the Arf-responsive, PIP2-dependent phospholipase D1". Biochemical and Biophysical Research Communications 235 (3): 854–9. Jun 1997. doi:10.1006/bbrc.1997.6793. PMID 9207251. 
  11. ↑ "Activation of phospholipase D1 by direct interaction with ADP-ribosylation factor 1 and RalA". FEBS Letters 430 (3): 231–5. Jul 1998. doi:10.1016/S0014-5793(98)00661-9. PMID 9688545. 
  12. ↑ "Ral GTPases regulate exocyst assembly through dual subunit interactions". The Journal of Biological Chemistry 278 (51): 51743–8. Dec 2003. doi:10.1074/jbc.M308702200. PMID 14525976. 
  13. ↑ "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. Sep 1995. doi:10.1074/jbc.270.38.22473. PMID 7673236. 
  14. ↑ "Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases". Molecular and Cellular Biology 15 (8): 4578–84. Aug 1995. doi:10.1128/mcb.15.8.4578. PMID 7623849. 
  15. ↑ "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. Jan 1998. doi:10.1074/jbc.273.2.814. PMID 9422736. 

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: P11233 (Ras-related protein Ral-A) at the PDBe-KB.




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