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J. Biol. Chem., Vol. 282, Issue 52, 37747-37758, December 28, 2007

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53BP2S, Interacting with Insulin Receptor Substrates, Modulates Insulin Signaling^*

Fumihiko Hakuno, Shigekazu Kurihara¹, Robert T. Watson, Jeffrey E. Pessin, and Shin-Ichiro Takahashi²

From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan and the Department of Pharmacological Sciences, State University of New York, Stony Brook, New York 11794

It is well known that insulin receptor substrates (IRS) act as a mediator for signal transduction of insulin, insulin-like growth factors, and several cytokines. To identify proteins that interact with IRS and modulate IRS-mediated signals, we performed yeast two-hybrid screening with IRS-1 as bait. Out of 109 cDNA-positive clones identified from a human placental cDNA library, two clones encoded 53BP2, p53-binding protein 2 (53BP2S), a short form splicing variant of the apoptosis-stimulating protein of p53 that possesses Src homology region 3 domain, and ankyrin repeats domain, and had been reported to interact with p53, Bcl-2, and NF-B. Interaction of 53BP2S with IRS-1 was confirmed by glutathione S-transferase pull-down and co-immunoprecipitation assays in COS-7 cells and 3T3-L1 adipocytes. The Src homology region 3 domain and ankyrin repeats domain of 53BP2S were responsible for its interaction with IRS-1, whereas the phosphotyrosine binding domain and a central domain (amino acid residues 750-861) of IRS-1 were required for its interaction with 53BP2S. In CHO-C400 cells, expression of 53BP2S reduced insulin-stimulated IRS-1 tyrosine phosphorylation with a concomitant enhancement of IRS-2 tyrosine phosphorylation. In addition, the amount of the phosphatidylinositol 3-kinase regulatory p85 subunit associated with tyrosine-phosphorylated proteins, and activation of Akt was enhanced by 53BP2S expression. Although 53BP2S also enhanced Akt activation in 3T3-L1 adipocytes, insulin-induced glucose transporter 4 translocation was markedly inhibited in accordance with reduction of insulin-induced AS160 phosphorylation. Together these data demonstrate that 53BP2S interacts and modulates the insulin signals mediated by IRSs.

Received for publication, March 22, 2007 , and in revised form, July 30, 2007.

^* This work was supported in part by Grant-in-aid for International Joint Research 08044193 (to S.-I. T.), Grant-in-aid for Scientific Research A 16208028 (to S.-I. T.) from the Ministry of Education, Science, and Culture of Japan, and by the Program for Promotion of Basic Research Activities for Innovative Biosciences (to F. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address; Research Institute for Health Fundamentals, Ajinomoto Co. Inc., 1-1 Suzuki-cho, Kawasaki-shi, Kanagawa 210-8681, Japan.

² To whom correspondence should be addressed: Laboratory of Cell Regulation, Dept. of Applied Animal Sciences, Graduate School of Agriculture and Life Sciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. Tel.: 81-3-5841-1310; Fax: 81-3-5841-1311; E-mail: atkshin{at}mail.ecc.u-tokyo.ac.jp.

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