Somatostatin receptor 1 (SSTR1)-mediated inhibition of cell proliferation correlates with the activation of the MAP kinase cascade: role of the phosphotyrosine phosphatase SHP-2

The mitogen activated protein (MAP) kinase cascade represents one of the ma jor regulator of cell growth by hormones and growth factors. However, altho ugh the activation of this intracellular pathway has been often regarded as mediator of cell proliferation, in many cell types the increase in MAP kin ase (also called extra-cellular signal regulated kinase; ERK) activity may result in cell growth arrest, depending on the length or the intensity of t he stimulation. In this review we examine recent data concerning the effect s of somatostatin on the MAP kinase cascade through one of its major recept or subtype, the somatostatin receptor 1 (SSTR1), stably expressed in CHO-KI cells. Somatostatin inhibits the proliferative effects of basic FGF (bFGF) in CHO-SSTR1 cell line. However, in these cells, somatostatin robustly act ivates the MAP kinase and augments bFGF-induced stimulation of ERK. We show that the activation of ERK via SSTR1 is mediated by the py subunit of a pe rtussis toxin-sensitive G-protein and requires both the small G protein Pas and the serine/threonine kinase Raf-1. Moreover the phosphatidyl inositol- 3kinase and the cytosolic tyrosine kinase c-src participate in the signal t ransduction regulated by SSTR1 to activate ERK, as well as it is involved t he protein tyrosine phosphatase (PTP) SHP-2. Previous studies have suggeste d that somatostatin-stimulated PTP activity mediates the growth inhibitory actions of somatostatin, in CHO-SSTR1 cells. Thus, the activation of SHP-2 by SSTR1 may mediate the antiproliferative activity of somatostatin. SHP-2 may, in turn, regulate the activity of kinases upstream of ERK that require tyrosine dephosphorylation to be activated, such as c-src. Finally, the sy nergism between somatostatin and bFGF in the activation of ERK results in a n increased expression of the cyclin-dependent kinase inhibitor p2(cip1/WAF 1) as molecular effector of the antiproliferative activity of somatostatin. (C) 2000 Elsevier Science Ltd. Published by Editions scientifiques et medi cales Elsevier SAS.