Regulation of somatostatin receptor signaling (Schonbrunn) Somatostatin (SS) receptor 2A (sstr2A) is the most widely expressed SS receptor subtype in normal tissues and human tumors. It plays a critical physiological role in regulating pituitary, pancreatic and gastrointestinal hormone secretion, among many biological actions. It is also the therapeutic target for the SS analogs used to treat patients with pituitary and gastro-enteropancreatic neuroendocrine tumors in order to inhibit hormonal hyper-secretion and to reduce tumor growth. Unfortunately, a large fraction of patients are resistant to SS analog therapy from the start and others develop resistance during the course of treatment. The reasons for this are unknown. To increase our understanding of SS action and improve its therapeutic applications our long term goal is to elucidate the molecular events involved in SS receptor signaling and the mechanisms which regulate receptor function to produce target cell resistance. Our previous studies showed that hormone binding stimulates the rapid and specific phosphorylation of sstr2A at multiple Ser and Thr, which we have identified. Receptor phosphorylation alters both sstr2A signaling and subcellular trafficking, with specific phosphorylation sites exerting distinct effects on receptor function. Unexpectedly, the pattern of receptor phosphorylation varies dramatically with different ligands, including those currently in clinical trials. The objective of this proposal is to determine how the phosphorylation of sstr2A i controlled and how it affects receptor signaling and trafficking. The organizing hypothesis for these studies is that phosphorylation and dephosphorylation of sstr2A are stringently regulated in order to produce receptors with distinct patterns of phosphorylated residues - a so-called phosphorylation 'bar code'. We propose that these differentially phosphorylated receptors are generated in different cellular compartments and determine the interactions of the receptor with specific cytosolic proteins that then produce the cellular response to SS and SS analog stimulation. This hypothesis will be tested in four specific aims: (1) Determine how phosphorylation of specific Ser/Thr residues affects sstr2A trafficking and signaling, (2) Identifythe enzymes that regulate the phosphorylation state of the receptor. We will complete the identification of the kinases that phosphorylate sstr2A and will characterize the enzyme complexes that catalyze sstr2A dephosphorylation in a phosphosite- specific manner. We will also determine how specific phosphatases are directed to act on the receptor in particular subcellular compartments, (3) Elucidate the mechanisms that produce cell-type specific differences in sstr2A phosphorylation, trafficking, and signaling in pituitary and gastroenteropancreatic tumor cells, and (4) Elucidate the mechanisms responsible for agonist-specific sstr2A trafficking and desensitization. These studies will provide novel insights into thebiochemical and cellular processes which regulate sstr2A, as well as other G protein coupled receptors, and the manner in which different agonists and the cellular environment impact those processes.
Neuroendocrine tumors are detected and treated with drugs that recognize and activate the sst2A somatostatin receptor (sstr2A). The effectiveness of these drugs depends on the continued sensitivity of sstr2A to stimulation. Our basic studies will determine the molecular and cellular mechanisms that control the nature and the magnitude of sst2A receptor responses to somatostatin and to somatostatin analogs in clinical use and in development. The knowledge gained will provide important insights into the function of sstr2A in neuroendocrine tumors and the manner in which therapeutic somatostatin analogs affect receptor activity. Understanding these fundamental processes will facilitate the development of better drugs and interventions to prevent the development of tumor resistance to SS analog therapy and will be generally applicable to the use of drugs targeting the G protein coupled, seven-transmembrane domain receptor family.
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|Ghosh, Madhumita; Schonbrunn, Agnes (2011) Differential temporal and spatial regulation of somatostatin receptor phosphorylation and dephosphorylation. J Biol Chem 286:13561-73|