C-terminal region of human somatostatin receptor 5 is required for induction of Rb and G(1) cell cycle arrest

Ligand-activated somatostatin receptors (SSTRs) initiate cytotoxic or cytos tatic antiproliferative signals. We have previously shown that cytotoxicity leading to apoptosis was signaled solely via human (h) SSTR subtype 3, whe reas the other four hSSTR subtypes initiated a cytostatic response that led to growth inhibition. In the present study we characterized the antiprolif erative signaling mediated by hSSTR subtypes 1, 2, 4, and 5 in CHO-K1 cells , We report here that cytostatic signaling via these subtypes results in in duction of the retinoblastoma protein Rb and G(1) cell cycle arrest. Immuno blot analysis revealed an increase in hypophosphorylated form of Rb in agon ist-treated cells. The relative efficacy of these receptors to initiate cyt ostatic signaling was hSSTR5>hSSTR2>hSSTR4 similar to hSSTR1. Cytostatic si gnaling via hSSTR5 also induced a marginal increase in cyclin-dependent kin ase inhibitor p21, hSSTR5-initiated cytostatic signaling was G protein depe ndent and protein tyrosine phosphatase (PTP) mediated. Octreotide treatment induced a translocation of cytosolic PTP to the membrane, whereas it did n ot stimulate PTP activity when added directly to the cell membranes. C-tail truncation mutants of hSSTR5 displayed progressive loss of antiproliferati ve signaling proportional to the length of deletion, as reflected by the ma rked decrease in the effects of octreotide on membrane translocation of cyt osolic PTP, and induction of Rb and G(1) arrest, These data demonstrate tha t the C-terminal domain of hSSTR5 is required for cytostatic signaling that is PTP dependent and leads to induction of hypophosphorylated Rb and G(1) arrest.