Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12202/3161
Title: STRUCTURE, BIOSYNTHESIS AND PROCESSING OF THE MURINE INSULIN RECEPTOR
Authors: SALZMAN, ALAN
Keywords: Pharmacology.
Issue Date: 1987
Publisher: ProQuest Dissertations & Theses
Citation: Source: Dissertation Abstracts International, Volume: 48-08, Section: B, page: 2279.
Abstract: The biosynthetic pathway of the insulin receptor was studied in hormonally responsive murine 3T3-L1 adipocytes. The insulin receptor is a tetramer composed of two subunits (130 kDa) and two subunits (90 kDa). The subunit contains a high affinity insulin binding site. The subunit is a substrate for an insulin-stimulated autophosphorylation reaction. Using metabolic radiolabeling techniques and immunoprecipitation, two precursor polypeptides have been identified and characterized with apparent molecular weights of 180 kDa, the initial precursor, and 200 kDa, the insulin proreceptor. The proreceptor is proteolytically cleaved to form the mature subunits of the insulin receptor.;Protein processing inhibitors were used to explore the structural relationships of the precursors and subunits. Appearance of the initial precursor was inhibited by tunicamycin, an Asn-linked glycosylation inhibitor, suggesting that it contains Asn-linked carbohydrate. Treatment with monensin, a carboxylic ionophore which affects a variety of Golgi functions, resulted in the accumulation of the 200 kDa proreceptor as well as cleavage to apparently smaller subunits, {dollar}\alpha\sp\prime{dollar} (115 kDa) and {dollar}\beta\sp\prime{dollar} (85 kDa), without affecting receptor transport to the cell surface. Studies with glycosidases have demonstrated that the proreceptor is generated by post-translational Asn-linked glycosylation of the initial precursor. Following cleavage, the subunits undergo post-translational oligosaccharide processing steps inhibited by monensin; the inhibitor's effects can be reversed by altering cellular pH. No detectable O-linked carbohydrate is present on the insulin receptor.;Functional properties of insulin receptor precursors and altered subunits synthesized in the presence of monensin were studied. Both precursors can bind insulin in solution; however, cleavage is necessary for binding activity in the intact cell. Monensin treatment results in a decreased number of receptors which maintain a high affinity for insulin, undergo insulin-stimulated autophosphorylation, undergo hormone-dependent internalization and recycling, and can function in insulin-dependent metabolic processes.
URI: https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:8719446
https://hdl.handle.net/20.500.12202/3161
Appears in Collections:Albert Einstein College of Medicine: Doctoral Dissertations

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