sst2 somatostatin receptor mediates cell cycle arrest and induction of p27(Kip1) - Evidence for the role of SHP-1

Activation of the somatostatin receptor sst2 inhibits cell proliferation by a mechanism involving the stimulation of the protein-tyrosine phosphatase SHP-1, The cell cycle regulatory events leading to sst2-mediated growth arr est are not known. Here, we report that treatment of Chinese hamster ovary cells expressing sst2 with the somatostatin analogue, RC-160, led to G(1) c ell cycle arrest and inhibition of insulin-induced S-phase entry through in duction of the cyclin-dependent kinase inhibitor p27(Kip1). Consequently, a decrease of p27(Kip1)-cdk2 association, an inhibition of insulin-induced c yclin E-cdk2 kinase activity, and an accumulation of hypophosphorylated ret inoblastoma gene product (Rb) were observed. However, RC-160 had no effect on the p21(Waf1/Cip1) When sst2 was coexpressed with a catalytically inacti ve mutant SHP-1 in Chinese hamster ovary cells, mutant SHP-1 induced entry into cell cycle and down-regulation of p27(Kip1) and prevented modulation b y insulin and RC-160 of p27(Kip1) expression, p27(Kip1)-cdk2 association, c yclin E-cdk2 kinase activity, and the phosphorylation state of Rb. In mouse pancreatic acini, RC-160 reverted down-regulation of p27(Kip1) induced by a mitogen, and this effect did not occur in acini from viable motheaten (me (v)/me(v)) mice expressing a mutant SHP-1 with markedly deficient enzymes. These findings provide the first evidence that sst2 induces cell cycle arre st through the up-regulation of p27(Kip1) and demonstrate that SHP-1 is req uired for maintaining high inhibitory levels of p27(Kip1) and is a critical target of the insulin, and somatostatin signaling cascade, leading to the modulation of p27(Kip1).