Antiproliferative Role of SSTR2
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Antiproliferative Role of SSTR2

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 (Ref.1). Somatostatin acts via a family of five GPCRs (G-Protein-Coupled Receptors): SSTR1-SSTR5 (Somatostatin Receptors) that are variably expressed throughout numerous tissues ranging from the CNS (Central Nervous System) to the Endocrine and Immune Systems. Somatostatin antiproliferative action results either from inhibition of trophic or growth factors secretion or from interference with the normal Cell Cycle Progression. Among the five Somatostatin receptors, SSTR2 (Somatostatin Receptor-2) plays a critical role in the negative control of normal and Tumor cell growth (Ref.2).

The mechanism involved in transmission of the antiproliferative effects of the SSTR2 has been attributed to the activation of protein tyrosine phosphatases: SHP1 (Tyrosine Phosphatase Shp1) and SHP2 (Tyrosine Phosphatase Shp2) and the subsequent strong and transient stimulation of ERKs (Extracellular Signal-Regulated Kinases). Activation of SSTR2 by Somatostatin enhances ERK1/2 stimulation and increases the expression of p21(CIP1) (Cyclin Dependent Kinase Inhibitor-p21) or p27(KIP1) (Cyclin Dependent Kinase Inhibitor-p27) CKIs (Cyclin-dependent Kinase Inhibitors) which interfere with the Cell Cycle Progression of the concerned cell (Ref.2 & 3). ERK1/2 activation is achieved through the coordinated stimulation of several signaling molecules: SSTR2 activation mediates activation of the two small GTPases Ras and Rap1-GTP through a mechanism dependent on PI3K (Phosphatidylinositde-3 Kinase) and both SHP1 and SHP2 tyrosine phosphatases. SHP2 directly interacts with SSTR2 via ITIM (Immunoreceptor Tyrosine-based Inhibitory Motif) sequences and activation of SSTR2 results in SHP2 and consequent SHP1 activation. Both SHP1 and SHP2 participate in Ras and Rap1 GTP loading prior to ERK1 and ERK2 activation. The activation of the two small GTPases Rap1 and Ras is also mediated by the protein Somatostatin promotes G-Beta-Gamma dependent Src activation, concomitant with SSTR2 tyrosine hyperphosphorylation and SHP2 activation. Ras and Rap1 activate the MAPKK (Mitogen-Activated Protein Kinase Kinase) kinase BRaf (v-Raf Murine Sarcoma Viral Oncogene Homolog-B1) which then results in the activation of the MEKs (MAPK/ERK Kinases): MEK1 and MEK2 followed by the activation of ERK1 and/or ERK2. The transcription factor Elk1 is a major target of the ERKs in the Somatostatin-induced, SSTR2-mediated growh arrest (Ref. 4, 5 & 6).

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 (Activating Transcription Factor-2), is required to inhibit the cell growth. Amplification of these MAPK (Mitogen-Activated Protein Kinase) cascades by SSTR2 enables the induction of p21(CIP1), and p27(KIP1), which interact with CDKs (Cyclin-Dependent Kinases) associated with Cyclin-A, Cyclin-D1, Cyclin-D2, Cyclin-D3, and Cyclin-E to inhibit CDK activity and thus block Cell Cycle progression. A cGMP (cyclic Guanosine Monophosphate)-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 the tyrosine phosphatase SHP1. Activated SHP1 associates with NOS(Nitric Oxide Synthase) and dephosphorylates it, leading to nNOS activation and NO (Nitric Oxide) production. Endogenously produced NO activates soluble GC (Guanylate Cyclase), which converts GTP (Guanosine Triphosphate) to cGMP. Increased cGMP inhibits cell growth. The downstream effectors of nNOS--->NO--->cGMP signaling pathway remain to be elucidated (2, 3 & 7).

SSTR2 is implicated in the regulation of various functions including inhibition of hormone secretions, cell proliferation and gut motility, neurotransmission and behavior, and pathological situations such as tumor growth and inflammation. Widespread distribution of SSTR2 is observed in the central and peripheral nervous systems as well as in peripheral organs. 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 (Ref.1 & 8).