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M209521200v1
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Papers In Press, published online ahead of print January 10, 2003
J. Biol. Chem, 10.1074/jbc.M209521200
Submitted on September 17, 2002
Revised on January 8, 2003
Accepted on January 10, 2003

Insulin receptor substrate 1 regulation of sarco-endoplasmic reticulum calcium ATPase 3 in insulin-secreting beta -cells

Prabhakar D Borge and Bryan A Wolf

Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4399

Corresponding Author: wolfb{at}mail.med.upenn.edu

We have previously characterized an Insulin Receptor Substrate 1 (IRS-1) overexpressing beta -cell line. These beta -cells demonstrated elevated fractional insulin secretion and elevated cytosolic Ca2+ levels compared to wild-type and vector controls. This effect of IRS-1 may be mediated via an interaction with the sarco-endoplasmic reticulum calcium ATPase (SERCA). Here we demonstrate that IRS-1 and IRS-2 localize to an endoplasmic reticulum (ER) enriched fraction in beta -cells using subcellular fractionation. We also observe co-localization of both IRS-1 and IRS-2 with ER marker proteins using immunofluorescent confocal microscopy. Furthermore, immuno-electron microscopy studies confirm that IRS-1 and SERCA3b localize to vesicles derived from the ER. In CHO-T cells transiently transfected with SERCA3b alone or together with IRS-1, SERCA3b co-immunoprecipitates with IRS-1. This interaction is enhanced with insulin treatment. SERCA3b also co-immunoprecipitates with IRS-1 in wild-type and IRS-1 overexpressing beta -cell lines. Ca2+ uptake in ER-enriched fractions prepared from wild-type and IRS-1 overexpressing cell lines shows no significant difference, indicating that the previously observed decrease in Ca2+ uptake by IRS-1 overexpressing cells is not due to a defect in SERCA. Treatment of wild-type beta -cells with thapsigargin (Tg), an inhibitor of SERCA, resulted in an increase in glucose-stimulated fractional insulin secretion similar to that observed in IRS-1 overexpressing cells. The colocalization of IRS proteins and SERCA on the ER of beta -cells increases the likelihood that these proteins can interact with one another. Co-immunoprecipitation of IRS-1 and SERCA in CHO-T cells and beta -cells confirms that these proteins do indeed interact directly. Pharmacological inhibition of SERCA in beta -cells results in enhanced secretion of insulin. Taken together, our data suggest that interaction between IRS proteins and SERCA is an important regulatory step in insulin secretion.


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