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J Biol Chem, Vol. 274, Issue 35, 24987-24994, August 27, 1999

The Carboxyl Terminal Extension of the Drosophila Insulin Receptor Homologue Binds IRS-1 and Influences Cell Survival

From the Department of Anatomy and Cell Biology, State University of New York, Health Science Center, Brooklyn, New York 11203 and ^§ Pfizer, Inc., Central Research Division, Groton, Connecticut 06340-8002

The Drosophila insulin receptor (INR) homolog includes an extension of approximately 400 amino acids at the carboxyl-terminal end of its  subunit containing several tyrosine-based motifs known to mediate interactions with signaling proteins. In order to explore the role of this extension in INR function, mammalian expression vectors encoding either the complete INR  subunit (-Myc) or the INR  subunit without the carboxyl-terminal extension () were constructed, and the membrane-bound  subunits were expressed in 293 and Madin-Darby canine kidney cells in the absence of the ligand-binding  subunits. -Myc and proteins were constitutively active tyrosine kinases of 180 and 102 kDa, respectively. INR -Myc co-immunoprecipitated a phosphoprotein of 170 kDa identified as insulin receptor substrate-1 (IRS-1), whereas INR did not, suggesting that the site of interaction was within the carboxyl-terminal extension. IRS-1 was phosphorylated on tyrosine to a much greater extent in cells expressing INR -Myc than in parental or INR cells. Despite this, a variety of PTB or SH2 domain-containing signaling proteins, including IRS-2, mSos-1, Shc, p85 subunit of phosphatidylinositol 3-kinase, SHP-2, Raf-1, and JAK2, were not associated with the INR -Myc·IRS-1 complex. Overexpression of INR -Myc and kinases conferred an equivalent increase in cell proliferation in both 293 and Madin-Darby canine kidney cells, indicating that this growth response is independent of the carboxyl-terminal extension. However, INR -Myc-expressing cells exhibited enhanced survival relative to parental and cells, suggesting that the carboxyl-terminal extension, through its interaction with IRS-1, plays a role in the regulation of cell death.

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