The cell surface expression, intracellular trafficking, and signal transduction by the family of G protein coupled receptors is tightly regulated by numerous proteins that interact with receptor cytoplasmic domains. Mutations in or altered expression of these receptor interacting proteins (RIPs) disrupt the complexes that anchor the receptor and its effectors and thus perturb receptor localization, trafficking and stability and cause defective receptor signaling. Several RIPs have been shown to bind to the sst2A somatostatin (SS) receptor, the therapeutic target for the SS analogs used as primary medical therapy for pituitary and other hormone secreting neuroendocrine tumors. SS analogs slow tumor progression and inhibit the secretion of bioactive tumor products thereby controlling the debilitating and potentially life-threatening symptoms produced by hormone secreting tumors. Unfortunately, SS analogs fail to control hormone hyper-secretion in a large fraction of patients. The factors that cause variability in patient responsiveness to SS analog therapy are not understood but do not result from mutations in the sst2A receptor and cannot be explained by an absence of sst2A mRNA expression. The fundamental hypothesis for this application is that sst2A receptor interacting proteins play a critical role in the responsiveness of hormone secreting tumors to SS analogs and that the interaction of these proteins with the sst2A receptor is dynamically regulated. In this proposal we plan to identify proteins associated with the sst2A receptor in pituitary tumor cells and characterize the functional consequences of the identified interactions on the cell surface expression of the sst2A receptor, on its intracellular trafficking and stability, and on its ability to activate the signal transduction pathways known to mediate SS inhibition of pituitary hormone secretion. In addition, we will determine how the association between the sst2A receptor and its interacting partners is dynamically regulated both at the cell surface and within endocytic compartments. The proposed studies will provide new understanding into the molecular mechanisms that control sst2A receptor signaling, trafficking and expression. Moreover, our results will generate protein candidates whose essential functions may be perturbed in hormone secreting tumors and thus contribute to resistance to SS analog therapy. Finally, they may suggest potential targets for drugs that act downstream of the sst2A receptor to bypass defects in receptor signaling and thus allow improved control of hormonal hypersecretion by pituitary tumors.
This research will elucidate basic molecular mechanisms by which receptors for the brain hormone somatostatin control cellular responses. In addition to their great physiological importance for regulating the secretion of pituitary, pancreatic and gut hormones, somatostatin receptors are widely expressed in many types of hormone secreting tumors and drugs that target these receptors are used to prevent the deleterious, potentially fatal, effects of tumor secretion in these patients as well as control the growth of their tumors. The proposed research will generate new insights into how somatostatin receptors inhibit hormone-secreting tumors and how defects in somatostatin receptor signaling may explain why many patients with such tumors do not respond to somatostatin receptor targeting drugs.
| Rodriguez, Melissa; Frost, Jeffrey A; Schonbrunn, Agnes (2018) Real-Time Signaling Assays Demonstrate Somatostatin Agonist Bias for Ion Channel Regulation in Somatotroph Tumor Cells. J Endocr Soc 2:779-793 |
