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Regulation of Extracellular Signal-regulated Kinase Activity by p120 RasGAP Does Not Involve Its Pleckstrin Homology or Calcium-dependent Lipid Binding Domains but Does Require These Domains to Regulate Cell Proliferation¹

Banting and Best Department of Medical Research, Medical Genetics, University of Toronto [J. A. K.], and MDS Proteomics, Inc. [M. F. M.], Toronto, Ontario M9W 7H4, Canada

The gene encoding for p120 RasGAP, has been disrupted in mice (M. Henkemeyer et al., Nature (Lond.), 377: 695–701, 1995).In this study, using fibroblasts derived from these mouse embryos (Gap^-/-; P. van der Geer et al., Mol. Cell Biol., 17: 1840–1847, 1997), we demonstrate that mitogen-activated protein kinase (MAPK) activation is prolonged after epidermal growth factor (EGF), but not lysophosphatidic acid, stimulation as compared with wild-type cells. Furthermore, these cells exhibited a moderate increase in their proliferative rate and saturation density, as well as a limited ability to form colonies in soft agar. Stable cell lines expressing full-length p120^GAP not only restored the ability to down-regulate MAPK after EGF stimulation but also lowered their saturation densities. Similarly, expression of p120^GAP, missing either its pleckstrin homology (PH) or its calcium-dependent lipid binding (CaLB)/C2 domain, restored MAPK down-regulation and retained the ability to associate with p190 RhoGAP and to be phosphorylated by v-src but exhibited higher saturation densities similar to Gap^-/- cells. Our results, therefore, suggest that p120^GAP functions not only by down-regulating the Ras/MAPK pathway after growth factor stimulation but is also important in regulating cell proliferation that involves its PH and CaLB domains.

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