Ras-independent activation of Ral by a Ca(2+)-dependent pathway

Curr Biol. 1998 Jul 2;8(14):839-42. doi: 10.1016/s0960-9822(98)70327-6.


The RalA and RalB proteins comprise a distinct family of small GTPases [1]. 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 [2-5]. 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 [6-8]. Ral also binds to phospholipase D (PLD) and thus may play a role in signaling through phospholipids [9]. 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 [10,11], 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 Ca(2+)-dependent mechanism for the activation of Ral.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Calcium / metabolism*
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Fibroblasts
  • GTP-Binding Proteins / metabolism*
  • Ionomycin / pharmacology
  • Lysophospholipids / pharmacology
  • Mutagenesis, Site-Directed
  • Pertussis Toxin
  • Rats
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects
  • Transfection
  • Type C Phospholipases / antagonists & inhibitors
  • Virulence Factors, Bordetella / pharmacology
  • ral GTP-Binding Proteins
  • ras Proteins / chemistry
  • ras Proteins / metabolism*


  • Enzyme Inhibitors
  • Lysophospholipids
  • Ralb protein, rat
  • Recombinant Proteins
  • Virulence Factors, Bordetella
  • Ionomycin
  • Epidermal Growth Factor
  • Pertussis Toxin
  • Type C Phospholipases
  • GTP-Binding Proteins
  • ral GTP-Binding Proteins
  • ras Proteins
  • Calcium