Transforming potential and signal transduction of the human insulin-like growth factor I receptor.
Item
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Title
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Transforming potential and signal transduction of the human insulin-like growth factor I receptor.
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Identifier
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AAI9315486
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identifier
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9315486
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Creator
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Liu, Delong.
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Contributor
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Adviser: Lu-Hai Wang
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Date
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1993
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular | Biology, Microbiology
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Abstract
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Human insulin-like growth factor I receptor (hIGFR) is a transmembrane (TM) protein tyrosine kinase (PTK). The IGFR PTK domain shares high sequence homology with those of the insulin receptor and the ros oncoprotein of avian sarcoma virus UR2. To explore the potential of IGFR to induce cellular transformation, 10 mutants were constructed from human IGFR cDNA by mutating its extracellular (EC) or carboxy terminal sequences. Those mutants were fused in frame to the 5{dollar}\sp\prime{dollar} sequence of UR2 gag p19 and expressed in chicken embryo fibroblasts (CEF). The full length hIGFR was able to induce CEF transformation. A gag-IGFR fusion protein retaining 36 amino acids of the IGFR EC domain and the entire TM and cytoplasmic domains had an enhanced transforming potential, which is correlated with its increased tyrosine kinase activity. The EC 36 aa sequence of IGFR in the gag-IGFR exerts modulatory effects on the protein's transforming and tumorigenic potential. The 20 aa residues immediately upstream of the TM domain have an inhibitory effect on the tumorigenic potential of gag-IGFR. The elevated association of phosphatidylinositol (PI) 3-kinase activity with IGFR proteins seem to be correlated with the transforming potency of the IGFR mutant proteins. The most C-terminal 27 amino acids of IGFR were dispensable, further deletion of 20 or 60 amino acids drastically affected the PTK activity and transforming ability of the gag-IGFR fusion protein. Surprisingly, deletion of C-terminal 67 aa appears to have little effect. Association of PI 3-kinase with IGFR requires its kinase activity and correlates with its tyrosine phosphorylation. In summary, this thesis contains the following findings: (1) The EC sequence has negative effects on PTK activity, transforming and tumorigenic potential of the hIGFR; (2) The C-terminal sequence from 1250 to 1310 is critical for the above biological functions and biochemical properties of IGFR; (3) PI 3-kinase is involved in IGFR signal transduction. Association of PI 3-kinase with IGFR relies on kinase activity and/or tyrosine phosphorylation of IGFR.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
