Biology of Somatostatin

Somatostatin (SST) is a multifunctional peptide and its function including its biosynthesis, posttranslational processing, gene regulation, regulation of secretion, islet and hypothalamic somatostatin function, somatostatin metabolism, receptors, and somatostatin dysfunction in disease such as diabetes, cancer, and neurodegeneration. This proposal is the continuation of 4 separate projects dealing with processing of SST, structure and function of somatostatin receptors (SSTR), role of SST in neurodegeneration and functional interaction of SSTRs with receptor tyrosine kinases. SST exists in two isoforms SST-14 and SST-28, derived from the same precursor Pro-SST. Our efforts in this direction are to define the molecular mechanism involved in the processing of Pro-SST to SST and elucidate whether there is any sorting receptor involve in SST maturation. Since the biological effect of SST is mediated by five different receptors subtypes namely SSTR1-5 member of G-protein coupled receptor (GPCR), exhibited homo-and heterodimerization with enhanced signaling and distinct pharmacological properties than the native receptors. Consistent with these observations we would like to determine the functional consequences of SSTR heterodimerization. In the central nervous system SST function as neurotransmitter and neuromodulator. SST cellular content and SST positive neurons selectively preserved in Huntington's disease and gradually decreased in Alzheimer's disease. Accordingly, the role of individual SSTR subtypes in different model of neurodegenerative diseases will be determined. The use of SST analogs is clinically proven in the treatment of variety of tumor. In breast cancer decrease SSTR expression and Increased expression of epidermal growth factor receptors (EGFRs) is frequently seen. Here we would like to delineate the role of SST and SSTRs on EGF induced transactivation of EGFR and modulation of down stream signaling cascade.