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J. Biol. Chem., Vol. 281, Issue 51, 39071-39080, December 22, 2006

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Dephosphorylation by Default, a Potential Mechanism for Regulation of Insulin Receptor Substrate-1/2, Akt, and ERK1/2^*

Rachel Zhande¹, Wenshuo Zhang, Yanbin Zheng, Elisha Pendleton, Yu Li, Roberto D. Polakiewicz, and Xiao Jian Sun²

From the Section of Endocrinology, The University of Chicago, Chicago, Illinois 60637 and Cell Signaling Technology, Incorporated, Beverly, Massachusetts 01915

Protein phosphorylation is an important mechanism that controls many cellular activities. Phosphorylation of a given protein is precisely controlled by two opposing biochemical reactions catalyzed by protein kinases and protein phosphatases. How these two opposing processes are coordinated to achieve regulation of protein phosphorylation is unresolved. We have developed a novel experimental approach to directly study protein dephosphorylation in cells. We determined the kinetics of dephosphorylation of insulin receptor substrate-1/2, Akt, and ERK1/2, phosphoproteins involved in insulin receptor signaling. We found that insulin-induced ERK1/2 and Akt kinase activities were completely abolished 10 min after inhibition of the corresponding upstream kinases with PD98059 and LY294002, respectively. In parallel experiments, insulin-induced phosphorylation of Akt, ERK1/2, and insulin receptor substrate-1/2 was decreased and followed similar kinetics. Our findings suggest that these proteins are dephosphorylated by a default mechanism, presumably via constitutively active phosphatases. However, dephosphorylation of these proteins is overcome by activation of protein kinases following stimulation of the insulin receptor. We propose that, during acute insulin stimulation, the kinetics of protein phosphorylation is determined by the interplay between upstream kinase activity and dephosphorylation by default.

Received for publication, June 1, 2006 , and in revised form, October 26, 2006.

^* This work was supported in part by an American Diabetes Association research grant and by National Institutes of Health Grant R01 DK060128 (to X. J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Medical Biophysics, British Columbia Cancer Research Center, Vancouver, British Columbia V5Z 1L3, Canada.

² To whom correspondence should be addressed: The University of Chicago, M-266, MC1027, 5841 S. Maryland Ave., Chicago, IL 60637. Tel.: 773-702-9661; Fax: 773-834-0486; E-mail: xsun{at}medicine.bsd.uchicago.edu.

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