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J Biol Chem, Vol. 274, Issue 31, 22019-22024, July 30, 1999

p85/p110-type Phosphatidylinositol Kinase Phosphorylates Not Only the D-3, but Also the D-4 Position of the Inositol Ring

Makoto Funaki, Hideki Katagiri^§, Akira Kanda^§, Motonobu Anai^§, Masao Nawano^§, Takehide Ogihara, Kouichi Inukai^§, Yasushi Fukushima^§, Hiraku Ono^§, 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, Japan, the  Institute for Adult Disease, Asahi Life Foundation, 1-9-14, Nishishinjuku, Shinjuku-ku, Tokyo 160, Japan, and the ^¶ Third Department of Internal Medicine, Yamaguchi University School of Medicine, 1144 Kogushi, Ube, Yamaguchi 755, Japan

Activation of p85/p110-type phosphatidylinositol (PI) kinase has been implicated in various cellular activities. This PI kinase phosphorylates the D-4 position with a similar or higher efficiency than the D-3 position when trichloroacetic acid-treated cell membrane is used as a substrate, although it phosphorylates almost exclusively the D-3 position of the inositol ring in phosphoinositides when purified PI is used as a substrate. Furthermore, the lipid kinase activities of p110 for both the D-3 and D-4 positions were completely abolished by introducing kinase-dead point mutations in their lipid kinase domains (Kin and Kin, respectively). In addition, both PI 3- and PI 4-kinase activities of p110 and p110 immunoprecipitates were similarly inhibited by either wortmannin or LY294002, specific inhibitors of p110. Insulin induced phosphorylation of not only the D-3 position, but also the D-4 position. Indeed, overexpression of p110 in Sf9 or 3T3-L1 cells induced marked phosphorylation of the D-4 position to a level comparable to or much greater than that of D-3, whereas inhibition of endogenous p85/p110-type PI kinase via overexpression of dominant-negative p85 (p85) in 3T3-L1 adipocytes abolished insulin-induced synthesis of both. Thus, p85/p110-type PI kinase phosphorylates the D-4 position of phosphoinositides more efficiently than the D-3 position in vivo, and each of the D-3- or D-4-phosphorylated phosphoinositides may transmit signals downstream.

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