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J. Biol. Chem., Vol. 280, Issue 5, 3795-3801, February 4, 2005

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Interdependent Regulation of Insulin Receptor Kinase Activity by ADP and Hydrogen Peroxide^*

Thomas L. Schmitt, Agnes Hotz-Wagenblatt, Helmut Klein¶, and Wulf Dröge||

From the Divisions of Immunochemistry and Molecular Biophysics, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany and the ^¶Institute of Biochemistry, University of Cologne, Otto-Fischer-Strasse 12-14, D-50674 Cologne, Germany

Insulin signaling requires autophosphorylation of the insulin receptor kinase (IRK) domain. Using purified recombinant IRK fragments and the isolated intact insulin receptor, we show here that autophosphorylation is inhibited by ADP and that this effect is essentially reversed by hydrogen peroxide. Autophosphorylation was inhibited by hydrogen peroxide (60 µM) in the absence of ADP but enhanced in the presence of inhibitory concentrations of ADP (67 µM). Enhancement by hydrogen peroxide required direct interaction of hydrogen peroxide with the kinase domain and was not seen in insulin receptor mutants C1245A and C1308A. A similar enhancement was obtained in intact cells in the absence of insulin upon treatment with 1-(2-chloroethyl)-3-(2-hydroxyethyl)-1-nitrosourea, indicating that IRK activity can be alternatively enhanced by a shift in the thiol/disulfide redox status. Molecular modeling of the IRK domain indicated that the ATP-binding site becomes distorted after releasing the nucleotide unless the IRK domain is oxidatively derivatized at Cys¹²⁴⁵. Recent clinical studies suggest that these effects may play a role in obesity due to the fact that cytoplasmic creatine kinase in combination with phosphocreatine normally ensures rapid removal of ADP in muscle cells but not in fat cells.

Received for publication, September 9, 2004 , and in revised form, November 22, 2004.

^* 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.

^|| To whom correspondence should be addressed. Tel.: 49-6221-423-706; Fax: 49-6221-423-746; E-mail: W.Droege{at}DKFZ.de.

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