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Submitted on February 3, 2004
Accepted on July 6, 2004
Research Service, James A. Haley Veterans Hospital and the Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, and the Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts
* To whom correspondence should be addressed. E-mail: rfarese{at}hsc.usf.edu.
Insulin receptor substrates (IRSs) 1 and 2 are postulated to control the activation of phosphatidylinositol 3-kinase(PI3K)-dependent signaling factors, viz., atypical protein kinase C (aPKC) and PKB/Akt, that mediate metabolic effects of insulin. However, it is uncertain if aPKC and PKB are activated together or differentially in response to IRS-1 and IRS-2 activation in insulin-sensitive tissues. Presently, we examined insulin activation of aPKC and PKB in vastus lateralis muscle, adipocytes and liver in wild type and IRS-1 knockout mice, and observed striking tissue-specific differences. In muscle of IRS-1 knockout mice, the activation of both aPKC and PKB was markedly diminished. In marked contrast, only aPKC activation was diminished in adipocytes, and only PKB activation was diminished in liver. These results suggest that IRS-1 is required for: (a) activation of both aPKC and PKB in muscle; (b) aPKC, but not PKB, activation in adipocytes; and (c) PKB, but not aPKC, activation in liver. Presumably, IRS-2 or other PI3K activators account for the normal activation of aPKC in liver and PKB in adipocytes of IRS-1 knockout mice. These complexities in aPKC and PKB activation may be relevant to metabolic abnormalities seen in tissues in which IRS-1 or IRS-2 is specifically or predominantly downregulated.
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