Molecular mechanisms of antiproliferative effect of somatostatin: involvement of a tyrosine phosphatase.

A protein of 66 kd immunoreactive to anti-tyrosine phosphatase (PTP1C) antibodies coeluted with, and so may be associated with, somatostatin receptors (ssts) from rat pancreatic membranes. Also, anti-PTP1C antibodies immunoprecipitated functional ssts from pancreatic membranes, suggesting a PTP1C protein can associate with ssts at the membrane level. Somatostatin analog RC 160 had good affinity for sst2,3 and sst5 (IC50 = 0.2, 0.1, and 21 nmol/L) and low affinity for sst1 and sst4 (IC50 = 200 and 620 nmol/L), and induced rapid dose-dependent stimulation of PTP activity (maximal at 1 nmol/L and half maximal at 5 pmol/L) in NIH3T3 and CHO cells expressing sst2, with similar results for sst1, but no stimulation with sst3,4 or sst5. Treatment of cells expressing sst2 with RC 160 for 24 hours inhibited serum- or growth factor-induced cell proliferation dose-dependently (maximal at 1 nmol/L, half maximal at 6 to 53 pmol/L RC 160). In cells expressing sst1, weak inhibition of fibroblast growth factor 2-induced NIH3T3 cell proliferation was provoked by somatostatin analogs (> 10 nmol/L). The good correlation between inhibition of somatostatin binding, stimulation of PTP activity, and inhibition of cell proliferation implicates a PTP in growth inhibition mediated by sst2 and sst1.