Antiproliferative Role of Somatostatin Receptor 2

Somatostatin is a widely distributed peptide hormone that plays an important inhibitory role in several biological processes, including neurotransmission, exocrine and endocrine secretions and cell proliferation. The antiproliferative action of somatostatin results either from inhibition of trophic or growth factor secretion or from interference with the normal cell cycle progression. Among the five somatostatin receptors, somatostatin receptor-2 (SSTR2) plays a critical role in the negative control of normal and tumor cell growth.The mechanism involved in transmission of the antiproliferative effects of the SSTR2 has been attributed to the activation of protein tyrosine phosphatases: SHP1 and SHP2 and the subsequent strong and transient stimulation of ERKs. Activation of SSTR2 by somatostatin enhances ERK1/2 stimulation and increases the expression of cyclin dependent kinase inhibitors-p21CIP1 and p27KIP1 which interfere with cell cycle progression. ERK1/2 activation is achieved through the coordinated stimulation of several signaling molecules.SHP2 directly interacts with SSTR2 via immunoreceptor tyrosine-based inhibitory motif (ITIM) sequences resulting in the activation of SSTR2, which then results in SHP2 and consequent SHP1 activation. Both SHP1 and SHP2 participate in Ras and Rap1 GTP loading prior to ERK1 and ERK2 activation. SSTR2 activation mediates activation of Ras and Rap1 through a mechanism dependent on PI3K and both SHP1 and SHP2.The activation of Rap1 and Ras is also mediated by the protein Src. Somatostatin promotes G-β-γ dependent Src activation, concomitant with SSTR2 tyrosine hyperphosphorylation and SHP2 activation. Ras and Rap1 activate B-Raf which then results in the activation of ERK1/2. The transcription factor Elk1 is a major target of the ERKs in the somatostatin-induced, SSTR2-mediated growth arrest.Besides the ERK1/2 pathway, activation of p38 also participates in cell growth arrest induced by somatostatin. The sustained activation of ERKs together with prolonged activation of p38, which activates the transcription factor ATF2, is required to inhibit the cell growth. Amplification of these MAPK cascades by SSTR2 enables the induction of p21CIP1 and p27KIP1, which interact with CDKs. A cGMP-dependent Kinase pathway is also involved in this antiproliferative signal of the somatostatin-SSTR2 pathway. SHP1 is critical for SSTR2-mediated cGMP production which leads to G1 cell cycle arrest. After binding to SSTR2, somatostatin activates SHP1. Activated SHP1 associates with NOS and dephosphorylates it, leading to nNOS activation and NO production. Endogenously produced NO activates soluble GC, which converts GTP to cGMP. Increased cGMP inhibits cell growth. The downstream effectors of nNOS-NO-cGMP signaling pathway remain to be elucidated.SSTR2 is also highly expressed in the majority of human tumors, and has been found to play a critical role in the negative control of tumor cell growth and to act as a tumor suppressor gene for various types of cancer.