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Gene Review

RALGDS  -  ral guanine nucleotide dissociation...

Homo sapiens

Synonyms: KIAA1308, RGDS, RGF, Ral guanine nucleotide dissociation stimulator, Ral guanine nucleotide exchange factor, ...
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Disease relevance of RALGDS


High impact information on RALGDS

  • Candidate effectors for these pathways include RalGDS and phosphatidyl inositol 3' kinase, as well as several other Ras binding proteins the biochemical and biological properties of which are poorly understood [3].
  • We have developed a novel assay to monitor the active, GTP-bound form of Rap1 based on the differential affinity of Rap1GTP and Rap1GDP for the Rap binding domain of RalGDS (RBD) [4].
  • The hRGFP gene was used to produce an amphotropic vector producer cell line that demonstrated vibrant green fluorescence after excitation with blue light [5].
  • Bright, long-term expression of the hRGFP gene in living eukaryotic cells will advance the study of gene transfer, gene expression, and gene product function in vitro and in vivo particularly for human gene therapy applications [5].
  • Cells were generated containing a gene for an improved (humanized, red-shifted) version of the Aequorea victoria green fluorescent protein (hRGFP) from a retroviral vector [5].

Biological context of RALGDS

  • Here we report the identification of full-length cDNA clones for human RALGDS, isolated from a brain cDNA library [6].
  • The predicted protein has strong sequence homology to rat and murine isoforms of RALGDS in the N- and C-terminal regions, but an internal region (aa 250-380) shows relatively high divergence with only 42% identical amino acid residues [6].
  • Functional studies showed that merlin inhibits the RalGDS-induced RalA activation, the colony formation and the cell migration in mammalian cells [7].
  • RalGDS is a guanine nucleotide dissociation stimulator for Ral, which is a member of the Ras GTPase superfamily that regulates cellular proliferation, differentiation and transformation by mediating multiple signal transduction pathways [8].
  • In this paper, by comparison between the gene's genomic and cDNA seqence, we determined the structure of the gene, which showed that the reported human RalGDS transcribed from 18 exons [8].

Anatomical context of RALGDS

  • Microinjection of a mutant RalA(28N) protein thought to sequester RalGDS family members reduced DNA synthesis stimulated by Ras as well as cAMP-mediated DNA synthesis in two cell lines which respond to cAMP with mitogenesis [9].
  • Associations between Ras and RalGDS were observed in extracts prepared from thyroid cells [9].
  • We have used the yeast two hybrid system to identify proteins that interact with an oncogenic form of the TC21 protein. cDNA clones encoding the carboxy-terminal region of the RalGDS protein were isolated from human B-cell and HeLa cDNA libraries [10].
  • Stimulation of gene expression in neonatal rat ventricular myocytes by Ras is mediated by Ral guanine nucleotide dissociation stimulator (Ral.GDS) and phosphatidylinositol 3-kinase in addition to Raf [11].
  • Ral GDP dissociation stimulator (RalGDS), a putative effector protein of Ras, stimulated the GDP/GTP exchange reaction of the post-tanslationally lipid-modified but not the unmodified form of Ral in response to epidermal growth factor in COS cells [12].

Associations of RALGDS with chemical compounds


Physical interactions of RALGDS

  • Here, we report that RalGDS interacts with ras p21 in mammalian cells in response to an extracellular signal [14].
  • Moreover, RalGDS only binds to TC21 in its active, GTP-loaded configuration [10].

Regulatory relationships of RALGDS


Other interactions of RALGDS

  • Cloning and evaluation of RALGDS as a candidate for the tuberous sclerosis gene TSC1 [6].
  • Moreover, using purified proteins, we demonstrate the direct GTP-dependent interaction of the Ras-like GTPases with RalGDS-RBD and full-length RalGDS in vitro [17].
  • AF-6 contains two putative Ras-associating domains (RA domains) which are seen in several Ras effectors such as RalGDS and RIN1 [18].
  • These results suggest that RalGDS functions as an effector protein of ras p21 [14].
  • The interactions of H-Ras, R-Ras, and Rap1A with the Ras-binding domains (RBD) of the c-Raf kinase and of the Ral guanine nucleotide exchange factor (RGF) was studied biochemically in solution [19].

Analytical, diagnostic and therapeutic context of RALGDS

  • These domains from downstream effectors such as Raf and RalGDS preferentially bind the GTP-bound Ras proteins enabling their extraction and subsequent quantification by immunoblotting [20].
  • The interaction of two members of the Ras subfamily with two different effector proteins, namely Raf and RalGDS, were investigated using isothermal titration calorimetry and a fluorescence-based method [21].
  • The structure of the complex of Ras with the Ras-binding domain of its effector RalGDS (RGS-RBD), the first genuine Ras-effector complex, has been solved by X-ray crystallography [22].
  • Crystallization and preliminary crystallographic analysis of the Ras binding domain of RalGDS, a guanine nucleotide dissociation stimulator of the Ral protein [23].
  • Three (18.75%) patients had severe aortic valve regurgitation with RGF between 40% and 60% due to technical errors and their allografts had to be replaced.(ABSTRACT TRUNCATED AT 250 WORDS)[2]


  1. Interdependent action of RalGEF and Erk in Ras-induced primitive endoderm differentiation of F9 embryonal carcinoma cells. Verheijen, M.H., Wolthuis, R.M., Defize, L.H., den Hertog, J., Bos, J.L. Oncogene (1999) [Pubmed]
  2. Orthotopic transplantation of aortic valve allografts. Early hemodynamic results. Yankah, A.C., Sievers, H.H., Bürsch, J.H., Radtcke, W., Lange, P.E., Heintzen, P.H., Bernhard, A. The Thoracic and cardiovascular surgeon. (1984) [Pubmed]
  3. Signal transduction from multiple Ras effectors. Katz, M.E., McCormick, F. Curr. Opin. Genet. Dev. (1997) [Pubmed]
  4. Rapid Ca2+-mediated activation of Rap1 in human platelets. Franke, B., Akkerman, J.W., Bos, J.L. EMBO J. (1997) [Pubmed]
  5. Retroviral transfer and expression of a humanized, red-shifted green fluorescent protein gene into human tumor cells. Levy, J.P., Muldoon, R.R., Zolotukhin, S., Link, C.J. Nat. Biotechnol. (1996) [Pubmed]
  6. Cloning and evaluation of RALGDS as a candidate for the tuberous sclerosis gene TSC1. Humphrey, D., Kwiatkowska, J., Henske, E.P., Haines, J.L., Halley, D., van Slegtenhorst, M., Kwiatkowski, D.J. Ann. Hum. Genet. (1997) [Pubmed]
  7. The merlin tumor suppressor interacts with Ral guanine nucleotide dissociation stimulator and inhibits its activity. Ryu, C.H., Kim, S.W., Lee, K.H., Lee, J.Y., Kim, H., Lee, W.K., Choi, B.H., Lim, Y., Kim, Y.H., Lee, K.H., Hwang, T.K., Jun, T.Y., Rha, H.K. Oncogene (2005) [Pubmed]
  8. Structure characterization of human RalGDS gene, and the identification of its novel variant. Zheng, Q., Yu, L., Zhao, Y., Zhang, H., Fu, Q., Mao, N., Hu, P., Geng, Z., Zhao, S. Mol. Biol. Rep. (2000) [Pubmed]
  9. RalGDS functions in Ras- and cAMP-mediated growth stimulation. Miller, M.J., Prigent, S., Kupperman, E., Rioux, L., Park, S.H., Feramisco, J.R., White, M.A., Rutkowski, J.L., Meinkoth, J.L. J. Biol. Chem. (1997) [Pubmed]
  10. The TC21 oncoprotein interacts with the Ral guanosine nucleotide dissociation factor. López-Barahona, M., Bustelo, X.R., Barbacid, M. Oncogene (1996) [Pubmed]
  11. Stimulation of gene expression in neonatal rat ventricular myocytes by Ras is mediated by Ral guanine nucleotide dissociation stimulator (Ral.GDS) and phosphatidylinositol 3-kinase in addition to Raf. Fuller, S.J., Finn, S.G., Downward, J., Sugden, P.H. Biochem. J. (1998) [Pubmed]
  12. Colocalization of Ras and Ral on the membrane is required for Ras-dependent Ral activation through Ral GDP dissociation stimulator. Kishida, S., Koyama, S., Matsubara, K., Kishida, M., Matsuura, Y., Kikuchi, A. Oncogene (1997) [Pubmed]
  13. Interactions of the amino acid residue at position 31 of the c-Ha-Ras protein with Raf-1 and RalGDS. Shirouzu, M., Morinaka, K., Koyama, S., Hu, C.D., Hori-Tamura, N., Okada, T., Kariya, K., Kataoka, T., Kikuchi, A., Yokoyama, S. J. Biol. Chem. (1998) [Pubmed]
  14. Regulation of interaction of ras p21 with RalGDS and Raf-1 by cyclic AMP-dependent protein kinase. Kikuchi, A., Williams, L.T. J. Biol. Chem. (1996) [Pubmed]
  15. Identification of Ce-AF-6, a novel Caenorhabditis elegans protein, as a putative Ras effector. Watari, Y., Kariya, K., Shibatohge, M., Liao, Y., Hu, C.D., Goshima, M., Tamada, M., Kikuchi, A., Kataoka, T. Gene (1998) [Pubmed]
  16. Ectopic expression of constitutively activated Ral GTPase inhibits cell shape changes during Drosophila eye development. Sawamoto, K., Yamada, C., Kishida, S., Hirota, Y., Taguchi, A., Kikuchi, A., Okano, H. Oncogene (1999) [Pubmed]
  17. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Spaargaren, M., Bischoff, J.R. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  18. In vivo interaction of AF-6 with activated Ras and ZO-1. Yamamoto, T., Harada, N., Kawano, Y., Taya, S., Kaibuchi, K. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  19. Differential interaction of the ras family GTP-binding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ral-guanine nucleotide exchange factor. Herrmann, C., Horn, G., Spaargaren, M., Wittinghofer, A. J. Biol. Chem. (1996) [Pubmed]
  20. Measuring Ras-family GTP levels in vivo--running hot and cold. Castro, A.F., Rebhun, J.F., Quilliam, L.A. Methods (2005) [Pubmed]
  21. A detailed thermodynamic analysis of ras/effector complex interfaces. Kiel, C., Serrano, L., Herrmann, C. J. Mol. Biol. (2004) [Pubmed]
  22. Structural and biochemical analysis of Ras-effector signaling via RalGDS. Vetter, I.R., Linnemann, T., Wohlgemuth, S., Geyer, M., Kalbitzer, H.R., Herrmann, C., Wittinghofer, A. FEBS Lett. (1999) [Pubmed]
  23. Crystallization and preliminary crystallographic analysis of the Ras binding domain of RalGDS, a guanine nucleotide dissociation stimulator of the Ral protein. Huang, L., Jancarik, J., Kim, S.H., Hofer, F., Martin, G.S. Acta Crystallogr. D Biol. Crystallogr. (1996) [Pubmed]
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