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The activation of neuronal NO synthase is mediated by G-protein ß subunit and the tyrosine phosphatase SHP-2

PIERRE CORDELIER, JEAN-PIERRE ESTÈVE, NATHALIE RIVARD^*, MICHAEL MARLETTA, NICOLE VAYSSE, CHRISTIANE SUSINI and LOUIS BUSCAIL¹

INSERM U151, IFR 31, CHU Rangueil, 31403 Toulouse, France;
^* Département d'Anatomie et de Biologie Cellulaire, Faculté de Médecine, Université de Sherbrooke, Canada; and
Howard Hughes Medical Institute, The University of Michigan, Medical School, Ann Arbor, Michigan 48109-0606, USA

¹Correspondence: INSERM U151, Institut Louis Bugnard, 1 avenue J. Poulhès, CHU Rangueil, 31403 Toulouse, Cédex 4, France. E-mail: louis.buscail{at}rangueil.inserm.fr

In CHO cells we had found that CCK positively regulated cell proliferation via the activation of a soluble guanylate cyclase. Here we demonstrate that CCK stimulated a nitric oxide synthase (NOS) activity. The production of NO was involved in the proliferative response elicited by CCK regarding the inhibitory effect of NOS inhibitors L-NAME and -guanidinoglutaric acid. We identified the NOS activated by the peptide as the neuronal isoform: the expression of the C415A neuronal NOS mutant inhibited both CCK-induced stimulation of NOS activity and cell proliferation. These two effects were also inhibited after expression of the C459S tyrosine phosphatase SHP-2 mutant and the ßARK1 (495–689) sequestrant peptide, indicating the requirement of activated SHP-2 and G-ß subunit. Kinetic analysis (Western blot after coimmunoprecipitation and specific SHP-2 activity) revealed that in response to CCK-treatment, SHP-2 associated to G-ß1 subunit, became activated, and then dephosphorylated the neuronal NOS through a direct association. These data demonstrate that the neuronal NOS is implicated in proliferative effect evoked by CCK. A novel growth signaling pathway is described, involving the activation of neuronal NOS by dephosphorylation of tyrosyl residues.—Cordelier, P., Estève, J.-P., Rivard, N., Marletta, M., Vaysse, N., Susini, C., Buscail, L. The activation of neuronal no synthase is mediated by G-protein ß subunit and the tyrosine phosphatase SHP-2.

Key Words: cholecystokinin • nitric oxide • cell growth • Gß complex

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