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http://hdl.handle.net/11375/6171
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DC Field | Value | Language |
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dc.contributor.advisor | Rozakis-Adcock, Maria | en_US |
dc.contributor.author | Farhang-Fallah, Janet | en_US |
dc.date.accessioned | 2014-06-18T16:34:22Z | - |
dc.date.available | 2014-06-18T16:34:22Z | - |
dc.date.created | 2010-04-08 | en_US |
dc.date.issued | 2002 | en_US |
dc.identifier.other | opendissertations/1501 | en_US |
dc.identifier.other | 2192 | en_US |
dc.identifier.other | 1265959 | en_US |
dc.identifier.uri | http://hdl.handle.net/11375/6171 | - |
dc.description.abstract | <p>Insulin receptor substrate- I (IRS-I) protein is a major substrate of the insulin receptor tyrosine kinase and is essential for transducing many of the biological effects of insulin including mitogenesis, gene expression and glucose transport. The N-terrninus of IRS-1 contains a pleckstrin homology (PH) domain, followed by a phosphotyrosine-binding (PTB) domain that have been shown to co-operatively contribute in mediating productive receptor/substrate interactions. The PH domain is critical for recognition and subsequent phosphorylation of lRS-1 by the activated insulin receptor. In this thesis, the cloning and biochemical characterization of a novel protein, named PHIP (PH-interacting protein), has been described. PHIP binds selectively to the PH domain of lRS-1 in vitro, and stably associates with IRS-l ill vivo. Importantly, mutants of the IRS-1 PH domain that disrupt the PH fold fail to bind to PHIP. Anti-phosphotyrosine immunoblots of PHIP revealed no discernible insulin receptor-regulated phosphorylation, suggesting that PHIP is not itself a substrate of the insulin receptor. By contrast to full-length PHIP, overexpression of the PH-binding region of PHIP has a pronounced inhibitory effect on insulin-induced IRS-1 tyrosine phosphorylation levels. Moreover, expression of this dominant-negative PHIP mutant (DN/PHIP) leads to a marked attenuation of insulin-stimulated mitogen activated protein (MAP) kinase activity. Furthermore, overexpression of PHIP enhances insulin-induced transcriptional responses in a MAP Kinase-dependent manner. By contrast, DN/PHIP mutants specifically block mitogenic signals elicited by insulin and not serum.In addition, DN/PHIP mutant proteins also inhibit insulin-triggered GLUT4 translocation to the cell surface as well as actin assembly. It is therefore concluded that PHIP represents a physiological ligand of the IRS-1 PH domain which plays a critical role in insulin-stimulated biological responses mediated by IRS-1.</p> | en_US |
dc.subject | Biology | en_US |
dc.subject | Biology | en_US |
dc.title | Cloning and characterization of PHIP, a novel protein ligand of the PH domain of IRS-1 | en_US |
dc.type | thesis | en_US |
dc.contributor.department | Biology | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
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fulltext.pdf | 4.13 MB | Adobe PDF | View/Open |
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