Differential role of SH2-B and APS in regulating energy and glucose homeostasis

被引:40
作者
Li, M
Ren, DC
Iseki, M
Takaki, S
Rui, L [1 ]
机构
[1] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
[2] Univ Tokyo, Inst Med Sci, Dept Microbiol & Immunol, Div Immunol, Tokyo 1088639, Japan
关键词
D O I
10.1210/en.2005-1313
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
SH2-B and APS, two members of a pleckstrin homology and SH2 domain-containing adaptor family, promote both insulin and leptin signaling in a similar fashion in cultured cells. In addition, APS mediates insulin-stimulated activation of the c-Cbl/CAP/TC10 pathway in cultured adipocytes. Here we characterized genetically modified mice lacking SH2-B, APS, or both to determine the physiological roles of these two proteins in animals. Disruption of the SH2-B gene resulted in obesity, hyperglycemia, hyperinsulinemia, and glucose intolerance. Conversely, deletion of the APS gene did not alter adiposity, energy balance, and glucose metabolism. Energy intake, energy expenditure, fat content, body weight, and plasma insulin, leptin, glucose, and lipid levels were similar between APS(-/-) and WT littermates fed either normal chow or a high-fat diet. Moreover, deletion of APS failed to alter insulin and glucose tolerance. APS(-/-)/SH2-B-/- double knockout mice also developed energy imbalance, obesity, hyperleptinemia, hyperinsulinemia, hyperglycemia, and glucose intolerance; however, plasma leptin and insulin levels were significantly lower in APS(-/-)/SH2-B-/- than in SH2-B-/- mice. These results suggest that SH2-B, but not APS, is a key positive regulator of energy and glucose metabolism in mice.
引用
收藏
页码:2163 / 2170
页数:8
相关论文
共 34 条
[1]   The APS adapter protein couples the insulin receptor to the phosphorylation of c-Cbl and facilitates ligand-stimulated ubiquitination of the insulin receptor [J].
Ahmed, Z ;
Smith, BJ ;
Pillay, TS .
FEBS LETTERS, 2000, 475 (01) :31-34
[2]   Adapter protein with a pleckstrin homology (PH) and an Src homology 2 (SH2) domain (APS) and SH2-B enhance insulin-receptor autophosphorylation, extracellular-signal-regulated kinase and phosphoinositide 3-kinase-dependent signalling [J].
Ahmed, Z ;
Pillay, TS .
BIOCHEMICAL JOURNAL, 2003, 371 :405-412
[3]   Primary and essential role of the adaptor protein APS for recruitment of both c-Cbl and its associated protein CAP in insulin signaling [J].
Ahn, MY ;
Katsanakis, KD ;
Bheda, F ;
Pillay, TS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (20) :21526-21532
[4]   CAP defines a second signalling pathway required for insulin-stimulated glucose transport [J].
Baumann, CA ;
Ribon, V ;
Kanzaki, M ;
Thurmond, DC ;
Mora, S ;
Shigematsu, S ;
Bickel, PE ;
Pessin, JE ;
Saltiel, AR .
NATURE, 2000, 407 (6801) :202-207
[5]   Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice [J].
Chen, H ;
Charlat, O ;
Tartaglia, LA ;
Woolf, EA ;
Weng, X ;
Ellis, SJ ;
Lakey, ND ;
Culpepper, J ;
Moore, KJ ;
Breitbart, RE ;
Duyk, GM ;
Tepper, RI ;
Morgenstern, JP .
CELL, 1996, 84 (03) :491-495
[6]   Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10 [J].
Chiang, SH ;
Baumann, CA ;
Kanzaki, M ;
Thurmond, DC ;
Watson, RT ;
Neudauer, CL ;
Macara, IG ;
Pessin, JE ;
Saltiel, AR .
NATURE, 2001, 410 (6831) :944-948
[7]   Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor [J].
Chua, SC ;
Chung, WK ;
WuPeng, XS ;
Zhang, YY ;
Liu, SM ;
Tartaglia, L ;
Leibel, RL .
SCIENCE, 1996, 271 (5251) :994-996
[8]   A phenylalanine zipper mediates APS dimerization [J].
Dhe-Sirano, D ;
Werner, ED ;
Masahiro, N ;
Hansen, L ;
Chi, YI ;
Shoelson, SE .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2004, 11 (10) :968-974
[9]   SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin [J].
Duan, CJ ;
Li, MH ;
Rui, LY .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (42) :43684-43691
[10]   Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance [J].
Duan, CJ ;
Yang, HY ;
White, MF ;
Rui, LY .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (17) :7435-7443