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Volume 272, Number 39, Issue of September 26, 1997 pp. 24448-24454
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The Tyrosine Phosphatase SHP-1 Associates with the sst2 Somatostatin Receptor and Is an Essential Component of sst2-mediated Inhibitory Growth Signaling

(Received for publication, March 28, 1997, and in revised form, July 9, 1997)

Frédéric Lopez , Jean-Pierre Estève , Louis Buscail , Nathalie Delesque , Nathalie Saint-Laurent , Magali Théveniau , Clara Nahmias ^§ , Nicole Vaysse and Christiane Susini

From INSERM Unité 151, Institut Louis Bugnard, CHU Rangueil, F 31403 Toulouse Cedex, France,  Laboratoire de Génétique et Physiologie du développement, Luminy CASE 907, 13288 Marseille Cedex 9, France, and ^§ Institut Cochin de Génétique Moléculaire, 75014 Paris, France

Activation of the somatostatin receptor sst2, a member of the G_i protein-coupled receptor family, results in the stimulation of a protein-tyrosine phosphatase activity involved in the sst2-mediated growth inhibitory signal. Here, we report that SHP-1, a cytoplasmic protein-tyrosine phosphatase containing two Src homology 2 domains constitutively associated with sst2 as evidence by coprecipitation of SHP-1 protein with sst2, in Chinese hamster ovary cells coexpressing sst2 and SHP-1. Activation of sst2 by somatostatin resulted in a rapid dissociation of SHP-1 from sst2 accompanied by an increase of SHP-1 activity. SHP-1 was phosphorylated on tyrosine in control cells and somatostatin induced a rapid and transient dephosphorylation on tyrosine residues of the enzyme. Stimulation of SHP-1 activity by somatostatin was abolished by pertussis toxin pretreatment of cells. G_i3 was specifically immunoprecipitated by anti-sst2 and anti-SHP-1 antibodies, and somatostatin induced a rapid dissociation of G_i3 from sst2, suggesting that G_i3 may be involved in the sst2·SHP-1 complexes. Finally, somatostatin inhibited the proliferation of cells coexpressing sst2 and SHP-1, and this effect was suppressed in cells coexpressing sst2 and the catalytic inactive SHP-1 (C453S mutant). Our data identify SHP-1 as the tyrosine phosphatase associated with sst2 and demonstrate that this enzyme may be an initial key transducer of the antimitogenic signaling mediated by sst2.

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