Volume 272, Number 46, Issue of November 14, 1997 pp. 28829-28832
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
Ras-dependent Signaling by the GTPase-deficient Mutant of G₁₂

(Received for publication, August 5, 1997, and in revised form, September 18, 1997)

Sandra J. Wadsworth , Gerd Gebauer , George D. V. van Rossum ^§ and N. Dhanasekaran ^¶

From the  Fels Institute for Cancer Research and Molecular Biology, the ^§ Department of Pharmacology, and the ^¶ Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

G₁₂ and G₁₃ regulate diverse responses through the small GTPases Ras, CDC42, Rac, and Rho. Whereas they activate similar responses in many different cell types, they also activate more specific and critical signaling pathways in other cell types. In COS cells, in which both G₁₂ and G₁₃ stimulate Na⁺/H⁺ exchange, they do so by activating different signaling pathways. Here we report that the differential recruitment of specific small GTPases by G₁₂ and G₁₃ defines the molecular basis for their functional differences. We have observed that the stimulation of Na⁺/H⁺ exchange by the GTPase-deficient mutant of G₁₂ (G₁₂QL) requires a functional Ras and is independent of Rac/CDC42 and Jun kinase signaling module. By contrast, the stimulation of Na⁺/H⁺ exchange by G₁₃QL requires a functional Rac/CDC42 and the Jun kinase signaling module. Our results also indicate that G₁₂QL-Ras stimulation of Na⁺/H⁺ exchange involves a D609-sensitive phospholipase and protein kinase C. These studies, for the first time, describe a novel G₁₂-specific signaling pathway involving Ras, phosphatidylcholine hydrolysis, and protein kinase C in the regulation of Na⁺/H⁺ exchange.

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