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An Intracellular Multi-Effector Complex Mediates Somatostatin Receptor 1 Activation of Phospho-Tyrosine Phosphatase

Section of Pharmacology (S.A., A.P., A.M., T.F.), Department of Oncology, Biology and Genetics University of Genova 16132 Genova, Italy; Institut National de la Santé et de la Recherche Médicale, Unité 531 (J.-P.E., C.S.), Institut Fédératif de Recherche 31, Institut Louis Bugnard, 31432 Toulouse Cedex 4, France; Department of Experimental and Clinical Medicine (R.I.), University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy; and Department of Biology and Molecular and Cellular Pathology (A.F.), Consiglio Nazionale delle Ricerche Endocrinology and Experimental Oncology Center, University "Federico II" of Naples, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Tullio Florio, M.D., Ph.D., Sezione Farmacologia, Dipartimento Oncologia, Biologia e Genetica, Università di Genova, Viale Benedetto XV, 2, 16132 Genova, Italy. E-mail: tullio.florio{at}unige.it.

The receptor-like phosphotyrosine phosphatase (PTP) is an important intracellular effector of the cytostatic action of SST. Here we characterize, in Chinese hamster ovary-k1 cells, the intracellular pathway that from somatostatin receptor 1 (SSTR1), leads to the activation of PTP and that involves, in a multimeric complex and sequential activation, the tyrosine kinases Janus kinase (JAK) 2 and Src, and the cytosolic phosphotyrosine phosphatase SHP-2. We show that inhibitors of JAK2 and Src and dominant-negative mutants of SHP-2 and Src abolished the SSTR1-mediated PTP activation, suggesting that all these effectors participate in the activation of PTP. In basal conditions, JAK2 forms a multimeric complex with SHP-2, Src and PTP. In response to SST, JAK2 is activated in a G protein-dependent manner, dissociates from and phosphorylates SHP-2, increasing its activity. Subsequently, SHP-2 dissociates from Src, dephosphorylates the Src inhibitory tyrosine-529, and causes an autocatalytical increase of the phosphorylation of Src tyrosine 418, located inside its kinase activation loop. Active Src, in turn, controls the activity of PTP, via a direct interaction and phosphorylation of the phosphatase. These data for the first time depict an intracellular pathway involving a precise sequence of interactions and cross-activation among tyrosine phosphatases and kinases acting upstream of PTP. In particular the sequential activation of JAK2, SHP-2, and Src conveys the molecular signaling from SSTR1 to the activation of this phosphatase that is responsible for the final biological effects of SST.

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