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Ras-independent activation of Ral by a Ca2+-dependent pathway

1998; Elsevier BV; Volume: 8; Issue: 14 Linguagem: Inglês

10.1016/s0960-9822(98)70327-6

1879-0445

Franz Hofer, Rebecca Berdeaux, Greg S. Martin,

Retinal Development and Disorders

The RalA and RalB proteins comprise a distinct family of small GTPases [[1]Feig LA Emkey R Ral gene products and their regulation.in: Lacal JCL McCormick F The ras Superfamily of GTPases. CRC Press, Boca Raton1993: 247-257Google Scholar]. Ral-specific guanine-nucleotide exchange factors such as RalGDS, Rlf and RGL interact with activated Ras and cooperate with Ras in the transformation of murine fibroblasts [2Murai H Ikeda M Kishida S Ishida O Okazaki-Kishida M Matsuura Y et al.Characterization of Ral GDP dissociation stimulator-like (RGL) activities to regulate c-fos promoter and the GDP/GTP exchange of Ral.J Biol Chem. 1997; 272 (97256762): 10483-10490Crossref PubMed Scopus (55) Google Scholar, 3Urano T Emkey R Feig LA Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation.EMBO J. 1996; 15 (96181359): 810-816Crossref PubMed Scopus (294) Google Scholar, 4White MA Vale T Camonis JH Schaefer E Wigler MH A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation.J Biol Chem. 1996; 271 (96279201): 16439-16442Crossref PubMed Scopus (213) Google Scholar, 5Wolthuis RMF de Ruiter ND Cool RH Bos JL Stimulation of gene induction and cell growth by the Ras effector Rlf.EMBO J. 1997; 16 (98031902): 6748-6761Crossref PubMed Scopus (142) Google Scholar]. Thus, the interaction of RalGDS with Ras and the subsequent activation of Ral are thought to constitute a distinct Ras-dependent signaling pathway. The function of Ral is largely unknown. There is circumstantial evidence that Ral may have a function in regulating the cytoskeleton through its interaction with RIP1 (also known as RLIP or RalBP1), a GTPase-activating protein specific for the small GTPases Cdc42 and Rac [6Cantor SB Urano T Feig LA Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases.Mol Cell Biol. 1995; 15 (95349625): 4578-4584Crossref PubMed Scopus (252) Google Scholar, 7Jullien-Flores V Dorseuil O Romero F Letourneur F Saragosti S Berger R et al.Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity.J Biol Chem. 1995; 270 (95403450): 22473-22477Crossref PubMed Scopus (278) Google Scholar, 8Park SH Weinberg RA A putative effector of Ral has homology to Rho/Rac GTPase activating proteins.Oncogene. 1995; 11 (96112637): 2349-2355PubMed Google Scholar]. Ral also binds to phospholipase D (PLD) and thus may play a role in signaling through phospholipids [[9]Jiang H Luo JQ Urano T Frankel P Lu Z Foster DA et al.Involvement of Ral GTPase in v-Src-induced phospholipase D activation.Nature. 1995; 378 (96077115): 409-412Crossref PubMed Scopus (244) Google Scholar]. We have examined endogenous levels of activated, GTP-bound Ral (Ral–GTP) in Rat-2 fibroblasts stimulated with various mitogens. Lysophosphatidic acid (LPA) and epidermal growth factor (EGF), which activate both Ras-dependent and Ras-independent signaling pathways [10Berridge MJ Inositol trisphosphate and calcium signalling.Nature. 1993; 361 (93149269): 315-325Crossref PubMed Scopus (6067) Google Scholar, 11Moolenaar WH Kranenburg O Postma FR Zondag GC Lysophosphatidic acid: G-protein signalling and cellular responses.Curr Opin Cell Biol. 1997; 9 (97224241): 168-173Crossref PubMed Scopus (464) Google Scholar], rapidly activated Ral. Inhibition of Ras activation by dominant-negative Ras (RasS17N) or pertussis toxin had little effect on Ral–GTP levels, however. Ral was activated by the Ca2+ ionophore ionomycin, and activation by LPA or EGF could be blocked by a phospholipase C (PLC) inhibitor. The results presented here demonstrate a Ca2+-dependent mechanism for the activation of Ral.