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

J. Biol. Chem., Vol. 279, Issue 42, 43684-43691, October 15, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/42/43684    most recent M408495200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Duan, C. Articles by Rui, L. Search for Related Content PubMed PubMed Citation Articles by Duan, C. Articles by Rui, L. Social Bookmarking                      What's this?

SH2-B Promotes Insulin Receptor Substrate 1 (IRS1)- and IRS2-mediated Activation of the Phosphatidylinositol 3-Kinase Pathway in Response to Leptin^*

Chaojun Duan, Minghua Li, and Liangyou Rui

From the Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622

Leptin regulates energy homeostasis primarily by binding and activating its long form receptor (LRb). Deficiency of either leptin or LRb causes morbid obesity. Leptin stimulates LRb-associated JAK2, thus initiating multiple pathways including the Stat3 and phosphatidylinositol (PI) 3-kinase pathways that mediate leptin biological actions. Here we report that SH2-B, a JAK2-interacting protein, promotes activation of the PI 3-kinase pathway by recruiting insulin receptor substrate 1 (IRS1) and IRS2 in response to leptin. SH2-B directly bound, via its PH and SH2 domain, to both IRS1 and IRS2 both in vitro and in intact cells and mediated formation of a JAK2/SH2-B/IRS1 or IRS2 tertiary complex. Consequently, SH2-B dramatically enhanced leptin-stimulated tyrosine phosphorylation of IRS1 and IRS2 in HEK293 cells stably expressing LRb, thus promoting association of IRS1 and IRS2 with the p85 regulatory subunit of PI 3-kinase and phosphorylation and activation of Akt. SH2-B mutants with lower affinity for IRS1 and IRS2 exhibited reduced ability to promote association of JAK2 with IRS1, tyrosine phosphorylation of IRS1, and association of IRS1 with p85 in response to leptin. Moreover, deletion of the SH2-B gene impaired leptin-stimulated tyrosine phosphorylation of endogenous IRS1 in mouse embryonic fibroblasts (MEF), which was reversed by reintroduction of SH2-B. Similarly, SH2-B promoted growth hormone-stimulated tyrosine phosphorylation of IRS1 in both HEK293 and MEF cells. Our data suggest that SH2-B is a novel mediator of the PI 3-kinase pathway in response to leptin or other hormones and cytokines that activate JAK2.

Received for publication, July 27, 2004 , and in revised form, August 11, 2004.

^* This work was supported by Career Development Award 7-03-CD-11 from the American Diabetes Association, Grant RO1 DK 065122 from NIDDK, National Institutes of Health, and a Pilot and Feasibility Grant from the Michigan Diabetes Research and Training Center funded by Grant NIH5P60 DK20542 from NIDDK, National Institutes of Health. 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.

To whom correspondence should be addressed. Tel.: 734-615-7544; Fax: 734-647-9523; E-mail: ruily{at}umich.edu.

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

This article has been cited by other articles:

				J. Wauman, A.-S. De Smet, D. Catteeuw, D. Belsham, and J. Tavernier Insulin Receptor Substrate 4 Couples the Leptin Receptor to Multiple Signaling Pathways Mol. Endocrinol., April 1, 2008; 22(4): 965 - 977. [Abstract] [Full Text] [PDF]

				L. Chen, T. J. Maures, H. Jin, J. S. Huo, S. A. Rabbani, J. Schwartz, and C. Carter-Su SH2B1{beta} (SH2-B{beta}) Enhances Expression of a Subset of Nerve Growth Factor-Regulated Genes Important for Neuronal Differentiation Including Genes Encoding Urokinase Plasminogen Activator Receptor and Matrix Metalloproteinase 3/10 Mol. Endocrinol., February 1, 2008; 22(2): 454 - 476. [Abstract] [Full Text] [PDF]

				Z. Li, Y. Zhou, C. Carter-Su, M. G. Myers Jr., and L. Rui SH2B1 Enhances Leptin Signaling by Both Janus Kinase 2 Tyr813 Phosphorylation-Dependent and -Independent Mechanisms Mol. Endocrinol., September 1, 2007; 21(9): 2270 - 2281. [Abstract] [Full Text] [PDF]

				M. Diakonova, E. Helfer, S. Seveau, J. A. Swanson, C. Kocks, L. Rui, M.-F. Carlier, and C. Carter-Su Adapter Protein SH2-B{beta} Stimulates Actin-Based Motility of Listeria monocytogenes in a Vasodilator-Stimulated Phosphoprotein (VASP)-Dependent Fashion Infect. Immun., July 1, 2007; 75(7): 3581 - 3593. [Abstract] [Full Text] [PDF]

				D. Yoshiga, N. Sato, T. Torisu, H. Mori, R. Yoshida, S. Nakamura, G. Takaesu, T. Kobayashi, and A. Yoshimura Adaptor Protein SH2-B Linking Receptor-Tyrosine Kinase and Akt Promotes Adipocyte Differentiation by Regulating Peroxisome Proliferator-Activated Receptor {gamma} Messenger Ribonucleic Acid Levels Mol. Endocrinol., May 1, 2007; 21(5): 1120 - 1131. [Abstract] [Full Text] [PDF]

				M. Li, Z. Li, D. L. Morris, and L. Rui Identification of SH2B2{beta} as an Inhibitor for SH2B1- and SH2B2{alpha}-Promoted Janus Kinase-2 Activation and Insulin Signaling Endocrinology, April 1, 2007; 148(4): 1615 - 1621. [Abstract] [Full Text] [PDF]

				E. Mansour, F. G. Pereira, E. P. Araujo, M. E. C. Amaral, J. Morari, N. R. Ferraroni, D. S. Ferreira, I. Lorand-Metze, and L. A. Velloso Leptin Inhibits Apoptosis in Thymus through a Janus Kinase-2-Independent, Insulin Receptor Substrate-1/Phosphatidylinositol-3 Kinase-Dependent Pathway Endocrinology, November 1, 2006; 147(11): 5470 - 5479. [Abstract] [Full Text] [PDF]

				D. Lavens, T. Montoye, J. Piessevaux, L. Zabeau, J. Vandekerckhove, K. Gevaert, W. Becker, S. Eyckerman, and J. Tavernier A complex interaction pattern of CIS and SOCS2 with the leptin receptor J. Cell Sci., June 1, 2006; 119(11): 2214 - 2224. [Abstract] [Full Text] [PDF]

				S. R. Thorn, S. Purup, W. S. Cohick, M. Vestergaard, K. Sejrsen, and Y. R. Boisclair Leptin Does Not Act Directly on Mammary Epithelial Cells in Prepubertal Dairy Heifers J Dairy Sci, May 1, 2006; 89(5): 1467 - 1477. [Abstract] [Full Text] [PDF]

				M. Li, D. Ren, M. Iseki, S. Takaki, and L. Rui Differential Role of SH2-B and APS in Regulating Energy and Glucose Homeostasis Endocrinology, May 1, 2006; 147(5): 2163 - 2170. [Abstract] [Full Text] [PDF]

				Y. Zhang, W. Zhu, Y.-G. Wang, X.-J. Liu, L. Jiao, X. Liu, Z.-H. Zhang, C.-L. Lu, and C. He Interaction of SH2-B{beta} with RET is involved in signaling of GDNF-induced neurite outgrowth J. Cell Sci., April 15, 2006; 119(8): 1666 - 1676. [Abstract] [Full Text] [PDF]

				H. S. Elbatarny and D. H. Maurice Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex Am J Physiol Endocrinol Metab, October 1, 2005; 289(4): E695 - E702. [Abstract] [Full Text] [PDF]

				N. Martens, G. Uzan, M. Wery, R. Hooghe, E. L. Hooghe-Peters, and A. Gertler Suppressor of Cytokine Signaling 7 Inhibits Prolactin, Growth Hormone, and Leptin Signaling by Interacting with STAT5 or STAT3 and Attenuating Their Nuclear Translocation J. Biol. Chem., April 8, 2005; 280(14): 13817 - 13823. [Abstract] [Full Text] [PDF]