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Articles in PresS, published online ahead of print February 19, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00486.2001
Submitted on October 31, 2001
Accepted on February 1, 2002
1 Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan; Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan
2 Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi, Sendai, Japan
3 Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan
4 Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan
5 The Fourth Department of Medicine, Saitama Medical School, Moroyama, Iruma-gun, Saitama, Japan
6 The Institute for Adult Disease, Asahi Life Foundation, Shinjuku-ku, Tokyo, Japan
7 Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Meguro-ku, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: oka{at}int3.med.tohoku.ac.jp.
To investigate the role of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in the insulin signaling pathway for glucose metabolism, wild-type (wt) PDK1, the kinase-dead (kd), or the plecstrin homology domain deletion (
PH) mutant of PDK1, was expressed using an adenovirus gene transduction system in 3T3-L1 adipocytes. wt-PDK1 and kd-PDK1 were found in both membrane and cytosol fractions, while PH-PDK1, which exhibited PDK1 activity similar to that of wt-PDK1, was detected exclusively in the cytosol fraction. Insulin dose-dependently activated PKB, but did not change atypical PKC (aPKC) activity in control cells. aPKC activity was not affected by expression of wt, kd or PH-PDK1 in either the presence or the absence of insulin. Overexpression of wt-PDK1 enhanced insulin-induced activation of PKB as well as insulin-induced phosphorylation of glycogen synthase kinase (GSK) 3
/ß, a direct downstream target of PKB, although insulin-induced glycogen synthesis was not significantly enhanced by wt-PDK1 expression. Neither PH-PDK1 nor kd-PDK1 expression affected PKB activity, GSK3 phosphorylation or glycogen synthesis. Thus, membrane localization of PDK1 via its PH domain is essential for insulin signaling through the PDK1-PKB-GSK3/ßpathway. Glucose transport activity was unaffected by expression of wt-PDK1, kd-PDK1, or PH-PDK1 in either the presence or the absence of insulin. These findings suggest the presence of a signaling pathway for insulin-stimulated glucose transport, in which PDK1 to PKB or aPKC is not involved.
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