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Gene Review

Rala  -  v-ral simian leukemia viral oncogene...

Rattus norvegicus

Synonyms: Ral, Ral-a, Ras-related protein Ral-A
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Disease relevance of Rala


High impact information on Rala

  • In response to formyl-Met-Leu-Phe (fMLP) receptor stimulation, beta-arrestin Ral-GDS protein complexes dissociate and Ral-GDS translocates with beta-arrestin from the cytosol to the plasma membrane, resulting in the Ras-independent activation of the Ral effector pathway required for cytoskeletal rearrangement [5].
  • beta-Arrestins are important in chemoattractant receptor-induced granule release, a process that may involve Ral-dependent regulation of the actin cytoskeleton [5].
  • Ral GTPases regulate targeting of basolateral proteins in epithelial cells, secretagogue-dependent exocytosis in neuroendocrine cells and assembly of exocyst complexes [6].
  • We have identified the Ral GDP dissociation stimulator (Ral-GDS) as a beta-arrestin-binding protein by yeast two-hybrid screening and co-immunoprecipitation from human polymorphonuclear neutrophilic leukocytes (PMNs) [5].
  • The two Ral isoforms, RalA and -B, promote branching through distinct pathways, involving the exocyst complex and phospholipase D, respectively [7].

Chemical compound and disease context of Rala

  • The aim of this study was to see whether an estrogen-like compound, Raloxifene analog (LY117018 HCL, Ral) could likewise ameliorate CsA-induced osteopenia in the Ox rat [1].

Biological context of Rala

  • Here we report a novel regulatory mechanism for PLC-delta1 activation that involves direct interaction of the small GTPase Ral and the universal calcium-signaling molecule calmodulin (CaM) with PLC-delta1 [8].
  • Finally, Ral-dependent branching is mediated by protein kinase C-dependent phosphorylation of 43-kD growth-associated protein, a crucial molecule involved in pathfinding, plasticity, and regeneration [7].
  • In addition, depletion of endogenous Ral by RNA interference decreases branching in cortical neurons [7].
  • Ral proteins are members of the Ras superfamily of small GTPases and are involved in signalling pathways for actin cytoskeleton remodelling, cell cycle control, cellular transformation and vesicle transport [9].
  • RalBP1 binds specifically to the active GTP-bound form of RalA and not to a mutant Ral with a point mutation in its putative effector domain [10].

Anatomical context of Rala

  • Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex [7].
  • Our observation also demonstrates that the spatial regulation of RalA is conducted by a mechanism distinct from the temporal regulation conducted by Ras-dependent plasma membrane recruitment of Ral guanine nucleotide exchange factors [11].
  • We have examined endogenous levels of activated, GTP-bound Ral (Ral-GTP) in Rat-2 fibroblasts stimulated with various mitogens [12].
  • By using fluorescence resonance energy transfer-based probes for RalA activity, we found that the EGF-induced RalA activation in Cos7 cells was restricted at the EGF-induced nascent lamellipodia, whereas under a similar condition both Ras activation and Ras-dependent translocation of Ral GEFs occurred more diffusely at the plasma membrane [11].
  • They also implicate Ral GTPases and their related pathways in the assembly and function of the mitotic apparatus [13].

Associations of Rala with chemical compounds

  • Ral GTPases have been implicated as mediators of Ras-induced signal transduction from observations that Ral-specific guanine nucleotide exchange factors associate with Ras and are activated by Ras [14].
  • Lysophosphatidic acid (LPA) and epidermal growth factor (EGF), which activate both Ras-dependent and Ras-independent signaling pathways [10,11], rapidly activated Ral [12].
  • Ral was activated by the Ca2+ ionophore ionomycin, and activation by LPA or EGF could be blocked by a phospholipase C (PLC) inhibitor [12].
  • The growth stimulating effect of GS-DHN was enhanced in cells treated with antibodies directed against the glutathione conjugate transporters RLIP76 (Ral-binding protein) or the multidrug resistance protein-2 [15].
  • Oophorectomy caused a significant gain in weight in groups B and C which was prevented by Ral in groups D and E. Randomized blood glucose levels and 1,25(OH)2D3 levels were elevated in both CsA-treated groups [1].

Physical interactions of Rala

  • Here, we present the crystal structure of the Ral-binding domain of Exo84 in complex with active RalA [16].
  • Ral also binds to phospholipase D (PLD) and thus may play a role in signaling through phospholipids [9] [12].

Regulatory relationships of Rala


Other interactions of Rala

  • Thus, the Ral-CaM complex defines a multifaceted regulatory mechanism for PLC-delta1 activation [8].
  • Cytocentrin is a Ral-binding protein involved in the assembly and function of the mitotic apparatus [13].
  • Thus, the interaction of RalGDS with Ras and the subsequent activation of Ral are thought to constitute a distinct Ras-dependent signaling pathway [12].

Analytical, diagnostic and therapeutic context of Rala

  • Ral (group D) completely prevented the high turnover osteopenia caused by oophorectomy and was able to attenuate substantially the effects of CsA in the Ox rat (group E) [1].
  • Moreover, Ral activity was elevated in hypertrophied hearts (2.1-fold, P<0.01) by mechanical stress in association with increased CT-1 expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation in the rat aortic banding model [3].


  1. Raloxifene analog (LY117018 HCL) ameliorates cyclosporin A-induced osteopenia in oophorectomized rats. Bowman, A.R., Sass, D.A., Marshall, I., Ma, Y.F., Liang, H., Jee, W.S., Epstein, S. J. Bone Miner. Res. (1996) [Pubmed]
  2. The ras-related protein Ral is monoglucosylated by Clostridium sordellii lethal toxin. Hofmann, F., Rex, G., Aktories, K., Just, I. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  3. Ral GDP dissociation stimulator and Ral GTPase are involved in myocardial hypertrophy. Kawai, M., Kawashima, S., Sakoda, T., Toh, R., Kikuchi, A., Yamauchi-Takihara, K., Kunisada, K., Yokoyama, M. Hypertension (2003) [Pubmed]
  4. Inhibitory effects of carotenoids and retinoids on the in vitro growth of rat C-6 glioma cells. Wang, C.J., Lin, J.K. Proc. Natl. Sci. Counc. Repub. China B (1989) [Pubmed]
  5. Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Bhattacharya, M., Anborgh, P.H., Babwah, A.V., Dale, L.B., Dobransky, T., Benovic, J.L., Feldman, R.D., Verdi, J.M., Rylett, R.J., Ferguson, S.S. Nat. Cell Biol. (2002) [Pubmed]
  6. The exocyst is a Ral effector complex. Moskalenko, S., Henry, D.O., Rosse, C., Mirey, G., Camonis, J.H., White, M.A. Nat. Cell Biol. (2002) [Pubmed]
  7. Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex. Lalli, G., Hall, A. J. Cell Biol. (2005) [Pubmed]
  8. Regulation of phospholipase C-delta1 through direct interactions with the small GTPase Ral and calmodulin. Sidhu, R.S., Clough, R.R., Bhullar, R.P. J. Biol. Chem. (2005) [Pubmed]
  9. RalA interacts with ZONAB in a cell density-dependent manner and regulates its transcriptional activity. Frankel, P., Aronheim, A., Kavanagh, E., Balda, M.S., Matter, K., Bunney, T.D., Marshall, C.J. EMBO J. (2005) [Pubmed]
  10. Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases. Cantor, S.B., Urano, T., Feig, L.A. Mol. Cell. Biol. (1995) [Pubmed]
  11. RalA activation at nascent lamellipodia of epidermal growth factor-stimulated Cos7 cells and migrating Madin-Darby canine kidney cells. Takaya, A., Ohba, Y., Kurokawa, K., Matsuda, M. Mol. Biol. Cell (2004) [Pubmed]
  12. Ras-independent activation of Ral by a Ca(2+)-dependent pathway. Hofer, F., Berdeaux, R., Martin, G.S. Curr. Biol. (1998) [Pubmed]
  13. Cytocentrin is a Ral-binding protein involved in the assembly and function of the mitotic apparatus. Quaroni, A., Paul, E.C. J. Cell. Sci. (1999) [Pubmed]
  14. Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappaB. Henry, D.O., Moskalenko, S.A., Kaur, K.J., Fu, M., Pestell, R.G., Camonis, J.H., White, M.A. Mol. Cell. Biol. (2000) [Pubmed]
  15. Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE): role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth. Ramana, K.V., Bhatnagar, A., Srivastava, S., Yadav, U.C., Awasthi, S., Awasthi, Y.C., Srivastava, S.K. J. Biol. Chem. (2006) [Pubmed]
  16. Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. Jin, R., Junutula, J.R., Matern, H.T., Ervin, K.E., Scheller, R.H., Brunger, A.T. EMBO J. (2005) [Pubmed]
  17. Regulation of GTP-binding state in RalA through Ca2+ and calmodulin. Park, J.B. Exp. Mol. Med. (2001) [Pubmed]
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