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Originally published In Press as doi:10.1074/jbc.M205277200 on October 21, 2002

J. Biol. Chem., Vol. 277, Issue 52, 50386-50395, December 27, 2002
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A Dominant-negative p38 MAPK Mutant and Novel Selective Inhibitors of p38 MAPK Reduce Insulin-stimulated Glucose Uptake in 3T3-L1 Adipocytes without Affecting GLUT4 Translocation*

Romel SomwarDagger §, Sandra Koterski||, Gary SweeneyDagger **, Richard Sciotti||, Stevan Djuric||, Cathy Berg||, James Trevillyan||, Philipp E. SchererDagger Dagger , Christina M. Rondinone||, and Amira KlipDagger §§§

From the Dagger  Programme in Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, the § Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada, || Diabetes Research, Pharmaceutical Products Division, Abbott Laboratories, and Dagger Dagger  Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Participation of p38 mitogen-activated protein kinase (p38) in insulin-induced glucose uptake was suggested using pyridinylimidazole p38 inhibitors (e.g. SB203580). However, the role of p38 in insulin action remains controversial. We further test p38 participation in glucose uptake using a dominant-negative p38 mutant and two novel pharmacological p38 inhibitors related to but different from SB203580. We present the structures and activities of the azaazulene pharmacophores A291077 and A304000. p38 kinase activity was inhibited in vitro by A291077 and A304000 (IC50 = 0.6 and 4.7 µM). At higher concentrations A291077 but not A304000 inhibited JNK2alpha (IC50 = 3.5 µM). Pretreatment of 3T3-L1 adipocytes and L6 myotubes expressing GLUT4myc (L6-GLUT4myc myotubes) with A291077, A304000, SB202190, or SB203580 reduced insulin-stimulated glucose uptake by 50-60%, whereas chemical analogues inert toward p38 were ineffective. Expression of an inducible, dominant-negative p38 mutant in 3T3-L1 adipocytes reduced insulin-stimulated glucose uptake. GLUT4 translocation to the cell surface, immunodetected on plasma membrane lawns of 3T3-L1 adipocytes or on intact L6-GLUT4myc myotubes, was not altered by chemical or molecular inhibition of p38. We propose that p38 contributes to enhancing GLUT4 activity, thereby increasing glucose uptake. In addition, the azaazulene class of inhibitors described will be useful to decipher cellular actions of p38 and JNK.

* This work was supported in part by Research Grant MT1202 from the Canadian Institutes for Health Research (to A. K.) and by Grant IR01-DK55758 from the National Institutes of Health (to P. E. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a doctoral award from the Canadian Institutes for Health Research.

** Supported by a joint postdoctoral fellowship from the Banting and Best Diabetes Centre at the University of Toronto and Novo Nordisk Canada.

§§ To whom correspondence should be addressed: Programme in Cell Biology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-6392; Fax: 416-813-5028; E-mail: amira@sickkids.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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