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Molecular and Cellular Biology, March 2001, p. 1633-1646, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1633-1646.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Overexpression of SH2-Containing Inositol Phosphatase 2 Results in Negative Regulation of Insulin-Induced Metabolic Actions in 3T3-L1 Adipocytes via Its 5'-Phosphatase Catalytic Activity

Tsutomu Wada,1 Toshiyasu Sasaoka,1,2,* Makoto Funaki,3 Hiroyuki Hori,1 Shihou Murakami,1 Manabu Ishiki,1 Tetsuro Haruta,1 Tomoichiro Asano,4 Wataru Ogawa,5 Hajime Ishihara,1 and Masashi Kobayashi1

First Department of Internal Medicine1 and Department of Clinical Pharmacology,2 Toyama Medical and Pharmaceutical University, Toyama 930-0194, Institute for Adult Disease, Asahi Life Foundation, Shinjuku-ku, Tokyo 160-0023,3 Third Department of Internal Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655,4 and Second Department of Internal Medicine, Kobe University School of Medicine, Chuo-ku, Kobe 650-0017,5 Japan

Received 8 August 2000/Returned for modification 18 October 2000/Accepted 6 December 2000

Phosphatidylinositol (PI) 3-kinase plays an important role in various metabolic actions of insulin including glucose uptake and glycogen synthesis. Although PI 3-kinase primarily functions as a lipid kinase which preferentially phosphorylates the D-3 position of phospholipids, the effect of hydrolysis of the key PI 3-kinase product PI 3,4,5-triphosphate [PI(3,4,5)P3] on these biological responses is unknown. We recently cloned rat SH2-containing inositol phosphatase 2 (SHIP2) cDNA which possesses the 5'-phosphatase activity to hydrolyze PI(3,4,5)P3 to PI 3,4-bisphosphate [PI(3,4)P2] and which is mainly expressed in the target tissues of insulin. To study the role of SHIP2 in insulin signaling, wild-type SHIP2 (WT-SHIP2) and 5'-phosphatase-defective SHIP2 (Delta IP-SHIP2) were overexpressed in 3T3-L1 adipocytes by means of adenovirus-mediated gene transfer. Early events of insulin signaling including insulin-induced tyrosine phosphorylation of the insulin receptor beta  subunit and IRS-1, IRS-1 association with the p85 subunit, and PI 3-kinase activity were not affected by expression of either WT-SHIP2 or Delta IP-SHIP2. Because WT-SHIP2 possesses the 5'-phosphatase catalytic region, its overexpression marked by decreased insulin-induced PI(3,4,5)P3 production, as expected. In contrast, the amount of PI(3,4,5)P3 was increased by the expression of Delta IP-SHIP2, indicating that Delta IP-SHIP2 functions in a dominant-negative manner in 3T3-L1 adipocytes. Both PI(3,4,5)P3 and PI(3,4)P2 were known to possibly activate downstream targets Akt and protein kinase Clambda in vitro. Importantly, expression of WT-SHIP2 inhibited insulin-induced activation of Akt and protein kinase Clambda , whereas these activations were increased by expression of Delta IP-SHIP2 in vivo. Consistent with the regulation of downstream molecules of PI 3-kinase, insulin-induced 2-deoxyglucose uptake and Glut4 translocation were decreased by expression of WT-SHIP2 and increased by expression of Delta IP-SHIP2. In addition, insulin-induced phosphorylation of GSK-3beta and activation of PP1 followed by activation of glycogen synthase and glycogen synthesis were decreased by expression of WT-SHIP2 and increased by the expression of Delta IP-SHIP2. These results indicate that SHIP2 negatively regulates metabolic signaling of insulin via the 5'-phosphatase activity and that PI(3,4,5)P3 rather than PI(3,4)P2 is important for in vivo regulation of insulin-induced activation of downstream molecules of PI 3-kinase leading to glucose uptake and glycogen synthesis.

* Corresponding author. Mailing address: Department of Clinical Pharmacology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. Phone: 81-76-434-7287. Fax: 81-76-434-5025. E-mail: tsasaoka-tym{at}umin.ac.jp.

Molecular and Cellular Biology, March 2001, p. 1633-1646, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1633-1646.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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