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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 (
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
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
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
IP-SHIP2, indicating that
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 C
in vitro. Importantly, expression
of WT-SHIP2 inhibited insulin-induced activation of Akt and protein
kinase C
, whereas these activations were increased by expression of
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
IP-SHIP2. In addition, insulin-induced
phosphorylation of GSK-3
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
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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