HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 15, 14835-14843, April 9, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/15/14835    most recent M311534200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sasaoka, T. Articles by Kobayashi, M. Search for Related Content PubMed PubMed Citation Articles by Sasaoka, T. Articles by Kobayashi, M. Social Bookmarking                      What's this?

SH2-containing Inositol Phosphatase 2 Predominantly Regulates Akt2, and Not Akt1, Phosphorylation at the Plasma Membrane in Response to Insulin in 3T3-L1 Adipocytes^*

Toshiyasu Sasaoka¶, Tsutomu Wada||, Kazuhito Fukui||, Shihou Murakami||, Hajime Ishihara**, Ryo Suzuki, Kazuyuki Tobe, Takashi Kadowaki, and Masashi Kobayashi||

From the Department of Clinical Pharmacology and ^||First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan, ^**Sainou Hospital, Toyama 930-0887, Japan, and Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan

SH2-containing inositol phosphatase 2 (SHIP2) is a physiologically important negative regulator of insulin signaling by hydrolyzing the phosphatidylinositol (PI) 3-kinase product PI 3,4,5-trisphosphate in the target tissues of insulin. Targeted disruption of the SHIP2 gene in mice resulted in increased insulin sensitivity without affecting biological systems other than insulin signaling. Therefore, we investigated the molecular mechanisms by which SHIP2 specifically regulates insulin-induced metabolic signaling in 3T3-L1 adipocytes. Insulin-induced phosphorylation of Akt, one of the molecules downstream of PI3-kinase, was inhibited by expression of wild-type SHIP2, whereas it was increased by expression of 5'-phosphatase-defective (IP) SHIP2 in whole cell lysates. The regulatory effect of SHIP2 was mainly seen in the plasma membrane (PM) and low density microsomes but not in the cytosol. In this regard, following insulin stimulation, a proportion of Akt2, and not Akt1, appeared to redistribute from the cytosol to the PM. Thus, insulin-induced phosphorylation of Akt2 at the PM was predominantly regulated by SHIP2, whereas the phosphorylation of Akt1 was only minimally affected. Interestingly, insulin also elicited a subcellular redistribution of both wild-type and IP-SHIP2 from the cytosol to the PM. The degree of this redistribution was inhibited in part by pretreatment with PI3-kinase inhibitor. Although the expression of a constitutively active form of PI3-kinase myr-p110 also elicited a subcellular redistribution of SHIP2 to the PM, expression of SHIP2 appeared to affect the myr-p110-induced phosphorylation, and not the translocation, of Akt2. Furthermore, insulin-induced phosphorylation of Akt was effectively regulated by SHIP2 in embryonic fibroblasts derived from knockout mice lacking either insulin receptor substrate-1 or insulin receptor substrate-2. These results indicate that insulin specifically stimulates the redistribution of SHIP2 from the cytosol to the PM independent of 5'-phosphatase activity, thereby regulating the insulin-induced translocation and phosphorylation of Akt2 at the PM.

Received for publication, October 21, 2003 , and in revised form, January 13, 2004.

^* This work was supported in part by a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science (to T. S.). 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.

Contributed equally to this work.

^¶ To whom correspondence should be addressed: Dept. of Clinical Pharmacology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. Tel.: 81-76-434-7287; Fax: 81-76-434-5025; E-mail: tsasaoka-tym{at}umin.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Wada, S. Ohshima, E. Fujisawa, D. Koya, H. Tsuneki, and T. Sasaoka Aldosterone Inhibits Insulin-Induced Glucose Uptake by Degradation of Insulin Receptor Substrate (IRS) 1 and IRS2 via a Reactive Oxygen Species-Mediated Pathway in 3T3-L1 Adipocytes Endocrinology, April 1, 2009; 150(4): 1662 - 1669. [Abstract] [Full Text] [PDF]

				M. Ikubo, T. Wada, K. Fukui, M. Ishiki, H. Ishihara, T. Asano, H. Tsuneki, and T. Sasaoka Impact of lipid phosphatases SHIP2 and PTEN on the time- and Akt-isoform-specific amelioration of TNF-{alpha}-induced insulin resistance in 3T3-L1 adipocytes Am J Physiol Endocrinol Metab, January 1, 2009; 296(1): E157 - E164. [Abstract] [Full Text] [PDF]

				E. A. Ananieva, G. E. Gillaspy, A. Ely, R. N. Burnette, and F. L. Erickson Interaction of the WD40 Domain of a Myoinositol Polyphosphate 5-Phosphatase with SnRK1 Links Inositol, Sugar, and Stress Signaling Plant Physiology, December 1, 2008; 148(4): 1868 - 1882. [Abstract] [Full Text] [PDF]

				A. Mandl, D. Sarkes, V. Carricaburu, V. Jung, and L. Rameh Serum Withdrawal-Induced Accumulation of Phosphoinositide 3-Kinase Lipids in Differentiating 3T3-L6 Myoblasts: Distinct Roles for Ship2 and PTEN Mol. Cell. Biol., December 1, 2007; 27(23): 8098 - 8112. [Abstract] [Full Text] [PDF]

				W.-H. Leung and S. Bolland The Inositol 5'-Phosphatase SHIP-2 Negatively Regulates IgE-Induced Mast Cell Degranulation and Cytokine Production J. Immunol., July 1, 2007; 179(1): 95 - 102. [Abstract] [Full Text] [PDF]

				R. Buettner, I. Ottinger, C. Gerhardt-Salbert, C. E. Wrede, J. Scholmerich, and L. C. Bollheimer Antisense oligonucleotides against the lipid phosphatase SHIP2 improve muscle insulin sensitivity in a dietary rat model of the metabolic syndrome Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1871 - E1878. [Abstract] [Full Text] [PDF]

				L. M. Ooms, C. G. Fedele, M. V. Astle, I. Ivetac, V. Cheung, R. B. Pearson, M. J. Layton, A. Forrai, H. H. Nandurkar, and C. A. Mitchell The Inositol Polyphosphate 5-Phosphatase, PIPP, Is a Novel Regulator of Phosphoinositide 3-Kinase-dependent Neurite Elongation Mol. Biol. Cell, February 1, 2006; 17(2): 607 - 622. [Abstract] [Full Text] [PDF]

				F. S. L. Thong, C. B. Dugani, and A. Klip Turning Signals On and Off: GLUT4 Traffic in the Insulin-Signaling Highway Physiology, August 1, 2005; 20(4): 271 - 284. [Abstract] [Full Text] [PDF]

				K. Fukui, T. Wada, S. Kagawa, K. Nagira, M. Ikubo, H. Ishihara, M. Kobayashi, and T. Sasaoka Impact of the Liver-Specific Expression of SHIP2 (SH2-Containing Inositol 5'-Phosphatase 2) on Insulin Signaling and Glucose Metabolism in Mice Diabetes, July 1, 2005; 54(7): 1958 - 1967. [Abstract] [Full Text] [PDF]

				X. Tang, A. M. Powelka, N. A. Soriano, M. P. Czech, and A. Guilherme PTEN, but Not SHIP2, Suppresses Insulin Signaling through the Phosphatidylinositol 3-Kinase/Akt Pathway in 3T3-L1 Adipocytes J. Biol. Chem., June 10, 2005; 280(23): 22523 - 22529. [Abstract] [Full Text] [PDF]

				H. J. Herr, J. R. Bernard, D. W. Reeder, D. A. Rivas, J. J. Limon, and B. B. Yaspelkis III Insulin-stimulated plasma membrane association and activation of Akt2, aPKC {zeta} and aPKC {lambda} in high fat fed rodent skeletal muscle J. Physiol., June 1, 2005; 565(2): 627 - 636. [Abstract] [Full Text] [PDF]

				C. Huang, A. C. P. Thirone, X. Huang, and A. Klip Differential Contribution of Insulin Receptor Substrates 1 Versus 2 to Insulin Signaling and Glucose Uptake in L6 Myotubes J. Biol. Chem., May 13, 2005; 280(19): 19426 - 19435. [Abstract] [Full Text] [PDF]

				S. Kagawa, T. Sasaoka, S. Yaguchi, H. Ishihara, H. Tsuneki, S. Murakami, K. Fukui, T. Wada, S. Kobayashi, I. Kimura, et al. Impact of Src Homology 2-Containing Inositol 5'-Phosphatase 2 Gene Polymorphisms Detected in a Japanese Population on Insulin Signaling J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2911 - 2919. [Abstract] [Full Text] [PDF]

				Y. Wang, R. J. Keogh, M. G. Hunter, C. A. Mitchell, R. S. Frey, K. Javaid, A. B. Malik, S. Schurmans, S. Tridandapani, and C. B. Marsh SHIP2 Is Recruited to the Cell Membrane upon Macrophage Colony-Stimulating Factor (M-CSF) Stimulation and Regulates M-CSF-Induced Signaling J. Immunol., December 1, 2004; 173(11): 6820 - 6830. [Abstract] [Full Text] [PDF]

				G. Sweeney, R. R. Garg, R. B. Ceddia, D. Li, M. Ishiki, R. Somwar, L. J. Foster, P. O. Neilsen, G. D. Prestwich, A. Rudich, et al. Intracellular Delivery of Phosphatidylinositol (3,4,5)-Trisphosphate Causes Incorporation of Glucose Transporter 4 into the Plasma Membrane of Muscle and Fat Cells without Increasing Glucose Uptake J. Biol. Chem., July 30, 2004; 279(31): 32233 - 32242. [Abstract] [Full Text] [PDF]