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Insulin Receptor Kinase-Associated Phosphotyrosine Phosphatases in Hepatic Endosomes: Assessing the Role of Phosphotyrosine Phosphatase-1B

Polypeptide Hormone Laboratory (C.L., G.B., B.I.P.) and Department of Anatomy and Cell Biology (A.F., J.J.M.B., B.I.P.), McGill Cancer Center, and Department of Biochemistry, McGill University (F.G., M.L.T.), Montréal, Québec, Canada H3A 2B2

Address all correspondence and requests for reprints to: Dr Barry I. Posner, Room W315, Strathcona Building, 3640 University Street, Montréal, Québec, Canada H3A 2B2. E-mail: barry.posner{at}staff.mcgill.ca.

Previous work has shown that bisperoxo(1,10-phenanthroline)-oxovanadate(v) anion [bpV(phen)] induces potent insulin-mimicking effects in the rat, selectively activates the endosomal (EN) insulin receptor kinase (IRK) in liver, and markedly abolishes endosomal IRK-associated phosphotyrosine phosphatase (PTP) activity while reducing that of total ENs by approximately 30%. In this study we examined the relatively selective effect of bpv(phen) on endosomal PTP activities for the purpose of defining IRK-associated PTP(s). Using an in-gel PTP assay, we detected multiple (20) species of endosomal PTP (30 to >220 kDa), with five that were markedly inhibited after in vivo bpV(phen) administration. Using a combination of Mono Q anionic exchange chromatography and immunoblotting, we demonstrated that LAR (leukocyte common antigen-related), PTP-, and PTP-1B were present in endosomal subfractions not significantly inhibited by bpv(phen). PTP-1B activity was assayed in immunoprecipitates from hepatic ENs of control and bpV(phen)-treated rats and was found to be inhibited by approximately 30% after bpv(phen) treatment. To clarify the role of PTP-1B in dephosphorylating IRK, we prepared hepatic ENs from wild-type and PTP-1B-null mice. We found that the phosphotyrosine content of IRK was similar in these two types of ENs, and that IRK dephosphorylation was not affected in ENs from PTP-1B-null mice compared with that in ENs from wild-type mice. These data suggest that LAR , PTP-, and PTP-1B are not candidates for the IRK-associated PTP in hepatic ENs, and that IRK dephosphorylation in ENs may result from the concerted actions of several PTPs.

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