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J Biol Chem, Vol. 273, Issue 45, 29686-29692, November 6, 1998
Different Subcellular Distribution and Regulation of Expression
of Insulin Receptor Substrate (IRS)-3 from Those of IRS-1 and
IRS-2
Motonobu
Anai ,
Hiraku
Ono,
Makoto
Funaki ,
Yasushi
Fukushima,
Kouichi
Inukai ,
Takehide
Ogihara,
Hideyuki
Sakoda,
Yukiko
Onishi,
Yoshio
Yazaki,
Masatoshi
Kikuchi ,
Yoshitomo
Oka§, and
Tomoichiro
Asano
From The Third Department of Internal Medicine, Faculty of
Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, the
Institute for Adult Diseases, Asahi Life Foundation,
1-9-14 Nishishinjuku, Shinjuku-ku, Tokyo 116, and the
§ Third Department of Internal Medicine, Yamaguchi
University School of Medicine, 1144 Kogushi, Ube,
Yamaguchi 755, Japan
Adipocytes contain three major substrate proteins
of the insulin receptor, termed IRS-1, IRS-2, and IRS-3. We
demonstrated that IRS-1 and IRS-2 are located mainly in the low density
microsome (LDM) fraction and are tyrosine phosphorylated in response to insulin stimulation, leading to phosphatidylinositol (PI) 3-kinase activation. In contrast, IRS-3 is located mainly in the plasma membrane
(PM) fraction and contributes to PI 3-kinase activation in the PM
fraction. The different cellular localizations of IRS proteins may
account for the mechanism of insulin resistance induced by a high fat
diet, considering that PI 3-kinase activation in the LDM fraction is
reportedly essential for the translocation of GLUT4 in adipocytes. High
fat feeding in rats increased both protein and mRNA levels of IRS-3
but decreased those of IRS-1 and IRS-2 in epididymal adipocytes. As a
result, selective impairment of insulin-induced PI 3-kinase activation
was observed in the LDM fraction, whereas PI 3-kinase activation was
conserved in the PM fraction. This is the first report showing that
different IRS proteins function in different subcellular compartments,
which may contribute to determining the insulin sensitivity in adipocytes.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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