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Volume 271, Number 45, Issue of November 8, 1996 pp. 28677-28681
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Mutant of Insulin Receptor Substrate-1 Incapable of Activating Phosphatidylinositol 3-Kinase Did Not Mediate Insulin-stimulated Maturation of Xenopus laevis Oocytes

(Received for publication, February 21, 1996, and in revised form, July 30, 1996)

Ritsuko Yamamoto-Honda , Zen'ichiro Honda ^§ , Kohjiro Ueki , Kazuyuki Tobe , Yasushi Kaburagi , Yoshihiko Takahashi , Hiroyuki Tamemoto , Takeshi Suzuki ^§ , Kohji Itoh ^§ , Yasuo Akanuma ^¶ , Yoshio Yazaki and Takashi Kadowaki

From the  Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan, the ^§ Department of Physical Therapy and Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan, and the ^¶ Institute for Diabetes Care and Research, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100, Japan

Insulin receptor substrate-1 (IRS-1) is rapidly phosphorylated on multiple tyrosine residues in response to insulin and binds several Src homology 2 domain-containing proteins, thereby initiating downstream signaling. To assess the tyrosine phosphorylation sites that mediate relevant downstream signaling and biological effects, we created site-directed mutants of IRS-1 and overexpressed them in the Xenopus laevis oocyte. In oocytes overexpressing IRS-1 or IRS-1-895F (Tyr-895 replaced with phenylalanine), insulin activated phosphatidylinositol (PI) 3-kinase, p70 S6 kinase, and mitogen-activated protein kinase and induced oocyte maturation. In contrast, in oocytes overexpressing IRS-1-4F (Tyr-460, Tyr-608, Tyr-939, and Tyr-987 of IRS-1 replaced with phenylalanine), insulin did not activate PI 3-kinase, p70 S6 kinase, and mitogen-activated protein kinase and failed to induce oocyte maturation. These observations indicate that in X. laevis oocytes overexpressing IRS-1, the association of PI 3-kinase rather than Grb2 (growth factor-bound protein 2) with IRS-1 plays a major role in insulin-induced oocyte maturation. Activation of PI 3-kinase may lie upstream of mitogen-activated protein kinase activation and p70 S6 kinase activation in response to insulin.

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