ral guanine nucleotide exchange factor


Summary: A guanine nucleotide exchange factor that stimulates the dissociation of GDP from RAL GTP-BINDING PROTEINS. It also has GDP exchange activity towards other MONOMERIC GTP-BINDING PROTEINS.

Top Publications

  1. Linnemann T, Kiel C, Herter P, Herrmann C. The activation of RalGDS can be achieved independently of its Ras binding domain. Implications of an activation mechanism in Ras effector specificity and signal distribution. J Biol Chem. 2002;277:7831-7 pubmed
    ..Conversely, the Ras x RalGDS complex has a short lifetime of 0.1 s and Rap1 forms a long-lived complex with RalGDS, possibly explaining its antagonistic effect on Ras. ..
  2. Hernández Muñoz I, Benet M, Calero M, Jimenez M, Diaz R, Pellicer A. rgr oncogene: activation by elimination of translational controls and mislocalization. Cancer Res. 2003;63:4188-95 pubmed
    ..These results indicate that rgr is activated when its tight translational controls are eliminated and increased expression allows its relocation to the plasma membrane, where efficient activation of RAS occurs. ..
  3. Lim K, Baines A, Fiordalisi J, Shipitsin M, Feig L, Cox A, et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell. 2005;7:533-45 pubmed
    ..Activation of RalA signaling thus appears to be a critical step in Ras-induced transformation and tumorigenesis of human cells...
  4. Shao H, Andres D. A novel RalGEF-like protein, RGL3, as a candidate effector for rit and Ras. J Biol Chem. 2000;275:26914-24 pubmed
    ..These data suggest that RGL3 functions as an exchange factor for Ral and may serve as a downstream effector for both Rit and Ras. ..
  5. Bhattacharya M, Anborgh P, Babwah A, Dale L, Dobransky T, Benovic J, et al. Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nat Cell Biol. 2002;4:547-55 pubmed
    ..Thus, beta-arrestins regulate multiple steps in the Ral-dependent processes that result in chemoattractant-induced cytoskeletal reorganization. ..
  6. Gohlke H, Kiel C, Case D. Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. J Mol Biol. 2003;330:891-913 pubmed
    ..This explains the finding of a conformational change in this region upon complex formation with Ras, and it may trigger a larger structural change in Raf, which is considered to be necessary for activation of the effector by Ras. ..
  7. De Ruiter N, Wolthuis R, van Dam H, Burgering B, Bos J. Ras-dependent regulation of c-Jun phosphorylation is mediated by the Ral guanine nucleotide exchange factor-Ral pathway. Mol Cell Biol. 2000;20:8480-8 pubmed
    ..These results suggest that the RalGEF-Ral pathway plays a major role in Ras-dependent c-Jun phosphorylation. Ral-dependent regulation of c-Jun phosphorylation includes JNK, a still elusive JNKK, and possibly Src. ..
  8. Hernández Muñoz I, Malumbres M, Leonardi P, Pellicer A. The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways. Oncogene. 2000;19:2745-57 pubmed
    ..Additional analysis has shown that the activation of this pathway by Rgr is not due to a feed back mechanism mediated by the Grb2 adaptor protein. Oncogene (2000). ..
  9. Kiel C, Serrano L, Herrmann C. A detailed thermodynamic analysis of ras/effector complex interfaces. J Mol Biol. 2004;340:1039-58 pubmed

More Information


  1. Cascone I, Selimoglu R, Ozdemir C, del Nery E, Yeaman C, White M, et al. Distinct roles of RalA and RalB in the progression of cytokinesis are supported by distinct RalGEFs. EMBO J. 2008;27:2375-87 pubmed publisher
    ..This suggests that Ral GTPases integrate diverse upstream signals to choreograph multiple roles for the exocyst in mitotic progression. ..
  2. Wolthuis R, Bauer B, van T Veer L, de Vries Smits A, Cool R, Spaargaren M, et al. RalGDS-like factor (Rlf) is a novel Ras and Rap 1A-associating protein. Oncogene. 1996;13:353-62 pubmed
    ..6 microM and 0.4 microM, respectively. No significant association with Ras-GDP or Rap 1A-GDP could be detected. These binding characteristics indicate that Rlf is a putative effector for Ras and Rap 1A. ..
  3. Albright C, Giddings B, Liu J, Vito M, Weinberg R. Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase. EMBO J. 1993;12:339-47 pubmed
    ..The 3600 nucleotide ralGDS mRNA and the 115 kDa protein were found in all tissues and cell lines examined. ..
  4. Senga T, Iwamoto T, Kitamura T, Miyake Y, Hamaguchi M. JAK/STAT3-dependent activation of the RalGDS/Ral pathway in M1 mouse myeloid leukemia cells. J Biol Chem. 2001;276:32678-81 pubmed
    ..An experiment using a Ras inhibitor demonstrated that full activation of RalA also requires activation of Ras. These results suggest a novel cross-talk between JAK/STAT3 and the Ras/RalGDS/Ral signaling pathways through gp130. ..
  5. Mirey G, Balakireva M, L Hoste S, Rosse C, Voegeling S, Camonis J. A Ral guanine exchange factor-Ral pathway is conserved in Drosophila melanogaster and sheds new light on the connectivity of the Ral, Ras, and Rap pathways. Mol Cell Biol. 2003;23:1112-24 pubmed
    ..Thus, in vivo data show variations in the connectivity of pathways described for cell lines which might display only a subset of the biological possibilities. ..
  6. Leonardi P, Kassin E, Hernández Muñoz I, Diaz R, Inghirami G, Pellicer A. Human rgr: transforming activity and alteration in T-cell malignancies. Oncogene. 2002;21:5108-16 pubmed
    ..These findings also raise the possibility that mutations in the hrgr gene are involved in other malignancies. ..
  7. Peterson S, Trabalzini L, Brtva T, Fischer T, Altschuler D, Martelli P, et al. Identification of a novel RalGDS-related protein as a candidate effector for Ras and Rap1. J Biol Chem. 1996;271:29903-8 pubmed
    ..We conclude that RGL2 may be an effector for Ras and/or Rap proteins. ..
  8. González García A, Pritchard C, Paterson H, Mavria G, Stamp G, Marshall C. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell. 2005;7:219-26 pubmed
    ..These studies identify RalGDS as a key component in Ras-dependent carcinogenesis in vivo. ..
  9. Rifki O, Bodemann B, Battiprolu P, White M, Hill J. RalGDS-dependent cardiomyocyte autophagy is required for load-induced ventricular hypertrophy. J Mol Cell Cardiol. 2013;59:128-38 pubmed publisher
    ..Together, these data implicate RalGDS-mediated induction of autophagy and exocyst function as a critical feature of load-induced cardiac hypertrophy. ..
  10. Hao Y, Wong R, Feig L. RalGDS couples growth factor signaling to Akt activation. Mol Cell Biol. 2008;28:2851-9 pubmed publisher
    ..Thus, RalGDS forms a nexus that transduces growth factor signaling to both Ral GTPase and Akt-mediated signaling cascades. ..
  11. Lebreton S, Boissel L, Moreau J. Control of embryonic Xenopus morphogenesis by a Ral-GDS/Xral branch of the Ras signalling pathway. J Cell Sci. 2003;116:4651-62 pubmed
    ..We conclude that Ral signalling is autonomously required by mesodermal cells to effect essential morphogenetic changes during Xenopus gastrulation. ..
  12. Rusanescu G, Gotoh T, Tian X, Feig L. Regulation of Ras signaling specificity by protein kinase C. Mol Cell Biol. 2001;21:2650-8 pubmed
    ..These findings identify a role for PKC in determining the specificity of Ras signaling by its ability to differentially modulate Ras effector protein activation. ..
  13. Yin J, Pollock C, Tracy K, Chock M, Martin P, Oberst M, et al. Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. Mol Cell Biol. 2007;27:7538-50 pubmed
    ..These data extend our understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis. ..
  14. Cheng G, Meinkoth J. Enhanced sensitivity to apoptosis in Ras-transformed thyroid cells. Oncogene. 2001;20:7334-41 pubmed
    ..Moreover, Ras expression results in a greater dependence of thyroid cells on MAPK and PI3K activity for their survival. ..
  15. Shima F, Kataoka T. [Critical role of posttranslational modification of Ras proteins in effector activation]. Seikagaku. 2005;77:519-26 pubmed
  16. Norman K, Hirasawa K, Yang A, Shields M, Lee P. Reovirus oncolysis: the Ras/RalGEF/p38 pathway dictates host cell permissiveness to reovirus infection. Proc Natl Acad Sci U S A. 2004;101:11099-104 pubmed
    ..We found that reovirus infection was blocked in the presence of the p38 inhibitor but not the JNK inhibitor. Together, these results implicate a Ras/RalGEF/p38 pathway in the regulation of reovirus replication and oncolysis. ..
  17. Carmena A, Makarova A, Speicher S. The Rap1-Rgl-Ral signaling network regulates neuroblast cortical polarity and spindle orientation. J Cell Biol. 2011;195:553-62 pubmed publisher
    ..In this paper, we show that the Ras-like small guanosine triphosphatase Rap1 signals through the Ral guanine nucleotide exchange factor Rgl and the PDZ protein Canoe (Cno; AF-6/Afadin in vertebrates) to modulate the NB division axis ..
  18. Eckardt N. Foolish seedlings and DELLA regulators: the functions of rice SLR1 and Arabidopsis RGL1 in GA signal transduction. Plant Cell. 2002;14:1-5 pubmed
  19. Isomura M, Okui K, Fujiwara T, Shin S, Nakamura Y. Isolation and mapping of RAB2L, a human cDNA that encodes a protein homologous to RalGDS. Cytogenet Cell Genet. 1996;74:263-5 pubmed
    ..Northern analysis revealed that the gene RAB2L is expressed in all human tissues examined. We assigned this gene locus to chromosome band 6p21.3 by fluorescence in situ hybridization. ..
  20. Shirouzu M, Morinaka K, Koyama S, Hu C, Hori Tamura N, Okada T, et al. Interactions of the amino acid residue at position 31 of the c-Ha-Ras protein with Raf-1 and RalGDS. J Biol Chem. 1998;273:7737-42 pubmed
    ..All of these results clearly show that the sharp contrast between the characteristics of Ras and Rap1A, with respect to the interactions with Raf-1 and RalGDS, depends on their residues at position 31. ..
  21. van Triest M, Bos J. Pull-down assays for guanoside 5'-triphosphate-bound Ras-like guanosine 5'-triphosphatases. Methods Mol Biol. 2004;250:97-102 pubmed
  22. Ehrhardt G, Korherr C, Wieler J, Knaus M, Schrader J. A novel potential effector of M-Ras and p21 Ras negatively regulates p21 Ras-mediated gene induction and cell growth. Oncogene. 2001;20:188-97 pubmed
    ..Thus, RPM/RGL3 is a novel potential effector of both p21 Ras and M-Ras with the novel function of negatively regulating Elk-1-dependent gene induction downstream of p21 Ras or MEKK-1. ..
  23. Gus Brautbar Y, Johnson D, Zhang L, Sun H, Wang P, Zhang S, et al. The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras. Mol Cell. 2012;45:610-8 pubmed publisher
    ..Thus, TIPE2 is an inhibitor of both inflammation and cancer, and a potential drug target for inflammatory and neoplastic diseases. ..
  24. Kang R, Kae H, Ip H, Spiegelman G, Weeks G. Evidence for a role for the Dictyostelium Rap1 in cell viability and the response to osmotic stress. J Cell Sci. 2002;115:3675-82 pubmed
    ..Rap1 was also activated in response to low temperature but not in response to low osmolarity or high temperature. ..
  25. Akasaka K. Highly fluctuating protein structures revealed by variable-pressure nuclear magnetic resonance. Biochemistry. 2003;42:10875-85 pubmed
    ..Detailed structural determination of higher-energy conformers with variable-pressure NMR will extend our knowledge of protein structure and conformational fluctuation over most of the biologically relevant conformational space. ..
  26. Gronwald W, Brunner K, Kirchhöfer R, Trenner J, Neidig K, Kalbitzer H. AUREMOL-RFAC-3D, combination of R-factors and their use for automated quality assessment of protein solution structures. J Biomol NMR. 2007;37:15-30 pubmed
  27. Miller M, Prigent S, Kupperman E, Rioux L, Park S, Feramisco J, et al. RalGDS functions in Ras- and cAMP-mediated growth stimulation. J Biol Chem. 1997;272:5600-5 pubmed
    ..These results support the idea that RalGDS may be an effector of Ras in cAMP-mediated growth stimulation. ..
  28. Poghosyan Z, Wynford Thomas D. Analysis of Ras transformation of human thyroid epithelial cells. Methods Enzymol. 2006;407:648-60 pubmed
  29. Inoue K, Maurer T, Yamada H, Herrmann C, Horn G, Kalbitzer H, et al. High-pressure NMR study of the complex of a GTPase Rap1A with its effector RalGDS. A conformational switch in RalGDS revealed from non-linear pressure shifts. FEBS Lett. 2001;506:180-4 pubmed
    ..It is considered likely that the conformational change from N to N' in the Ras-binding domain of RalGDS works as a switch to transmit the effector signal further to molecules of different RalGDS-dependent signaling pathways. ..
  30. Kfir S, Ehrlich M, Goldshmid A, Liu X, Kloog Y, Henis Y. Pathway- and expression level-dependent effects of oncogenic N-Ras: p27(Kip1) mislocalization by the Ral-GEF pathway and Erk-mediated interference with Smad signaling. Mol Cell Biol. 2005;25:8239-50 pubmed
    ..These findings have important implications for the contribution of activated Ras to oncogenesis and for the conversion of TGF-beta from an inhibitory to a metastatic factor in some epithelial tumors. ..
  31. Stang S, Bottorff D, Stone J. Interaction of activated Ras with Raf-1 alone may be sufficient for transformation of rat2 cells. Mol Cell Biol. 1997;17:3047-55 pubmed
    ..No evidence for cooperation between v-H-ras effector mutants was found. Signaling through the Raf1-MEK-mitogen-activated protein kinase cascade may be the only effector pathway contributing to RAS transformation in these cells. ..
  32. Ma Y, Zhang Q, Gu Y, Lu C, Chen J. Construction of chimeric E3s expression plasmids targeting oncoprotein ras. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2012;34:313-8 pubmed publisher
    ..1 can knocked down the protein level of Ras in PANC-1 cells. We successfully constructed the chimeric E3 expression plasmids, which provides a solid basis for further research on protein knockdown. ..
  33. Sato K, Ozawa S, Izukuri K, Kato Y, Hata R. Expression of tumour-suppressing chemokine BRAK/CXCL14 reduces cell migration rate of HSC-3 tongue carcinoma cells and stimulates attachment to collagen and formation of elongated focal adhesions in vitro. Cell Biol Int. 2010;34:513-22 pubmed publisher
  34. Fernández R, Ruiz Miró M, Dolcet X, Aldea M, Gari E. Cyclin D1 interacts and collaborates with Ral GTPases enhancing cell detachment and motility. Oncogene. 2011;30:1936-46 pubmed publisher
    ..In accordance with this, our data suggest that CycD1-Cdk4 enhances cell detachment and motility in collaboration with Ral GTPases. This new function may help explain the contribution of CycD1 to tumor spreading. ..
  35. Agapova L, Volodina J, Chumakov P, Kopnin B. Activation of Ras-Ral pathway attenuates p53-independent DNA damage G2 checkpoint. J Biol Chem. 2004;279:36382-9 pubmed
    ..The revealed function of the Ras-Ral pathway may contribute to the development of genetic instability in neoplastic cells. ..
  36. Ensign D, Webb L. Factors determining electrostatic fields in molecular dynamics simulations of the Ras/effector interface. Proteins. 2011;79:3511-24 pubmed publisher
    ..These calculations provide physical insight into the origin, magnitude, and importance of electrostatic fields in protein-protein interactions and suggest new experiments to probe the field's role in protein docking. ..
  37. Cheng H, Qin L, Lee S, Fu X, Richards D, Cao D, et al. Gibberellin regulates Arabidopsis floral development via suppression of DELLA protein function. Development. 2004;131:1055-64 pubmed
    ..GA thus promotes Arabidopsis petal, stamen and anther development by opposing the function of the DELLA proteins RGA, RGL1 and RGL2. ..
  38. Zheng X, Sanchez Fueyo A, Sho M, Domenig C, Sayegh M, Strom T. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity. 2003;19:503-14 pubmed
  39. Stafford A, Ensign D, Webb L. Vibrational Stark effect spectroscopy at the interface of Ras and Rap1A bound to the Ras binding domain of RalGDS reveals an electrostatic mechanism for protein-protein interaction. J Phys Chem B. 2010;114:15331-44 pubmed publisher
    ..These differences identify residues on the surface of RalGDS that direct the specificity of RalGDS binding to its in vivo binding partner, Rap1A, through an electrostatic mechanism. ..
  40. Maehama T, Tanaka M, Nishina H, Murakami M, Kanaho Y, Hanada K. RalA functions as an indispensable signal mediator for the nutrient-sensing system. J Biol Chem. 2008;283:35053-9 pubmed publisher
    ..These results collectively suggest that RalGDS and RalA act downstream of Rheb and that RalA activation is a crucial step in nutrient-induced mTORC1 activation. ..
  41. Kikuchi A, Demo S, Ye Z, Chen Y, Williams L. ralGDS family members interact with the effector loop of ras p21. Mol Cell Biol. 1994;14:7483-91 pubmed
    ..Therefore, ralGDS family members may be effector proteins of ras p21 or may inhibit interactions between ras p21 and its effectors. ..
  42. Yoshizaki H, Mochizuki N, Gotoh Y, Matsuda M. Akt-PDK1 complex mediates epidermal growth factor-induced membrane protrusion through Ral activation. Mol Biol Cell. 2007;18:119-28 pubmed
    ..These results identified the Akt-PDK1 complex as an upstream positive regulator of Ral GTPase in the induction of lamellipodial protrusion. ..
  43. Tsukamoto S, Ihara R, Aizawa A, Kishida S, Kikuchi A, Imai H, et al. Oog1, an oocyte-specific protein, interacts with Ras and Ras-signaling proteins during early embryogenesis. Biochem Biophys Res Commun. 2006;343:1105-12 pubmed
    ..We also examined the interaction between Oog1 and Ras by GST pull-down assay and revealed that Oog1 interacts with Ras in a GTP-dependent manner. These findings suggest a role of Oog1 as a Ras-binding protein. ..
  44. Hayes C, DeFeo K, Lan L, Paul B, Sell C, Gilmour S. Elevated levels of ornithine decarboxylase cooperate with Raf/ERK activation to convert normal keratinocytes into invasive malignant cells. Oncogene. 2006;25:1543-53 pubmed
    ..In order to promote invasiveness in keratinocytes, elevated levels of ODC may cooperate with Raf/ERK via activation of the Akt and Rho/Rac signaling pathway. ..
  45. Rodriguez Viciana P, McCormick F. RalGDS comes of age. Cancer Cell. 2005;7:205-6 pubmed
    ..Mice lacking RalGDS are defective in tumor formation, possibly because of increased apoptosis in Ras-driven tumors. The hunt for a clear role for RalGDS activation in human cancer is on. ..
  46. Rangarajan A, Hong S, Gifford A, Weinberg R. Species- and cell type-specific requirements for cellular transformation. Cancer Cell. 2004;6:171-83 pubmed
  47. Sawamoto K, Yamada C, Kishida S, Hirota Y, Taguchi A, Kikuchi A, et al. Ectopic expression of constitutively activated Ral GTPase inhibits cell shape changes during Drosophila eye development. Oncogene. 1999;18:1967-74 pubmed
    ..In addition, the phenotype was synergistically enhanced by the coexpression of RhoA. These results suggest that Ral functions to control the cytoskeletal structure required for cell shape changes during Drosophila development. ..
  48. Takaya A, Ohba Y, Kurokawa K, Matsuda M. RalA activation at nascent lamellipodia of epidermal growth factor-stimulated Cos7 cells and migrating Madin-Darby canine kidney cells. Mol Biol Cell. 2004;15:2549-57 pubmed
    ..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. ..
  49. Jaffe A, Aspenstrom P, Hall A. Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways. Mol Cell Biol. 2004;24:1736-46 pubmed
    ..Finally, hCNK1 associates with Rhophilin and RalGDS, Rho and Ras effector molecules, respectively, suggesting that it acts as a scaffold protein to mediate cross talk between the two pathways. ..
  50. Zheng Q, Yu L, Zhao Y, Zhang H, Fu Q, Mao N, et al. Structure characterization of human RalGDS gene, and the identification of its novel variant. Mol Biol Rep. 2000;27:209-16 pubmed
    ..Thus, the RalGDS gene consists of at least 19 exons and spanned a 44 kb region. The length between exon 1a and exon 2 was 33 kb, while the length between exon 1b and exon 2 was 8.8 kb. ..
  51. Ward Y, Wang W, Woodhouse E, Linnoila I, Liotta L, Kelly K. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways. Mol Cell Biol. 2001;21:5958-69 pubmed
    ..The generality of the role of the RalGEF pathway in metastasis is supported by the finding that Ras(12V,37G) increased the invasiveness of epithelial cells as well as fibroblasts. ..
  52. Wen C, Chang C. Arabidopsis RGL1 encodes a negative regulator of gibberellin responses. Plant Cell. 2002;14:87-100 pubmed
    ..These findings indicate that RGL1 is a partially redundant, but distinct, negative regulator of GA responses and suggest that all DELLA subfamily members might possess separate as well as overlapping roles in GA signaling. ..