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Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan,1 Department of Medicine, Division of Endocrinology, Howard Hughes Medical Institute, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts2
Received 28 March 2004/ Returned for modification 5 May 2004/ Accepted 3 June 2004
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ABSTRACT |
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INTRODUCTION |
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Recent structural studies suggest that dimeric APS binds to phosphorylated tyrosines within the activation loop of IR, contributing to IR activation (14). APS is a member of the SH2-B family of Src homology 2 (SH2) domain-containing proteins that includes SH2-B and Lnk. SH2-Bß was originally identified through its association with JAK2, a cytoplasmic tyrosine kinase that mediates cytokine actions (36). SH2-Bß is composed of a pleckstrin homology domain, an SH2 domain, and multiple phosphorylation sites. It binds to JAK2 via its SH2 domain, resulting in potentiation of JAK2 activation in response to growth hormone in cultured cells (32). SH2-Bß also binds via its SH2 domain to multiple receptor tyrosine kinases including receptors for insulin, insulin-like growth factor 1, platelet-derived growth factor, fibroblast growth factor, and nerve growth factor receptor TrkA (17, 18, 29, 30, 33, 35, 36). Alternative splicing of the SH2-B mRNA produces at least four isoforms (
, ß, 
, and 
) that differ in their C termini after the SH2 domain (25, 48); therefore, all isoforms are expected to bind to similar tyrosine kinases via their SH2 domains.
SH2-B binds via its SH2 domain to the activation loop of IR (18, 23, 25). Stable overexpression of SH2-B enhances insulin-stimulated activation of both Erk1/2 and Akt in Chinese hamster ovary cells (3). These observations raise the possibility that SH2-B may play a positive regulatory role during insulin action. In this work, we demonstrate that systemic deletion of the SH2-B gene severely impaired insulin signaling in skeletal muscle, the liver, and fat. Consequently, SH2-B–/– knockout mice progressively developed hyperinsulinemia, hyperglycemia, and glucose intolerance. Our results suggest that SH2-B is a physiological enhancer of insulin action and is required for glucose homeostasis during aging.
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MATERIALS AND METHODS |
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16 h) and D-glucose (2 g/kg of body weight) was injected intraperitoneally. Blood glucose was monitored at 0, 15, 30, 60, 90, 120, and 150 min after glucose injection. Immunoprecipitation and immunoblotting. Animals were anesthetized with Avertin (0.5 g of tribromoethanol and 0.25 g of tert-amyl alcohol in 39.5 ml of water; 0.02 ml/g of body weight) and treated for 5 min with either phosphate-buffered saline (PBS) or human insulin (3 U per mouse) via inferior vena cava injection. Liver, gastrocnemius muscle, and epididymal fat were isolated 5 min after stimulation and homogenized in lysis buffer (50 mM Tris [pH 7.5], 1% Nonidet P-40, 150 mM NaCl, 2 mM EGTA, 1 mM Na3VO4, 100 mM NaF, 10 mM Na4P2O7, 50 nM okadaic acid, 1 mM phenylmethylsulfonyl fluoride, 10 µg of aprotinin/ml, 10 µg of leupeptin/ml). Tissue extracts were incubated with indicated antibodies on ice for 2 h. The immune complexes were collected on protein A-agarose during a 1-h incubation at 4°C. The beads were washed three times with washing buffer (50 mM Tris [pH 7.5], 1% Nonidet P-40, 150 mM NaCl, 2 mM EGTA) and boiled for 5 min in a mixture (80:20) of lysis buffer and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) sample buffer (250 mM Tris-HCl [pH 6.8], 10% SDS, 10% ß-mercaptoethanol, 40% glycerol, 0.01% bromophenol blue). The solubilized proteins were separated by SDS-PAGE. Proteins on the gel were transferred to nitrocellulose membranes and detected by immunoblotting with the indicated antibodies by enhanced chemiluminescence. Some membranes were subsequently incubated at 55°C for 30 min in stripping buffer (100 mM ß-mercaptoethanol, 2% SDS, 62.5 mM Tris-HCl [pH 6.7]) to prepare them for reprobing.
Immunostaining. Mice were sacrificed by administering an overdose of sodium amino barbital (200 mg/kg of body weight). The pancreas was removed, cleared of fat and lymph nodes, fixed in Bouin's solution, and embedded in paraffin. Pancreatic sections (5 µm thick) were prepared, stained with hematoxylin and eosin or antibodies against insulin or glucagon, and photographed.
In vitro kinase assays.
Mice were treated with insulin (3 U) for 5 min as described above. For the IR kinase assay, the liver was isolated and homogenized in lysis buffer. The extracts were immunoprecipitated with anti-IR antibodies. After extensive washing, IR immunoprecipitates were incubated with [-32P]ATP (15 µCi) for 30 min at room temperature in reaction buffer (20 mM HEPES [pH 7.6], 5 mM MnCl2, 100 mM NaCl, 0.5 mM dithiothreitol, 1 mM Na3VO4, 5 mM MgCl2, 20 µM cold ATP, 10 µg of aprotinin/ml, 10 µg of leupeptin/ml). The reaction was stopped by adding 10 mM EDTA. The reaction mixture was resolved by SDS-PAGE and subsequently subjected to autoradiography. For the PI 3-kinase assay, gastrocnemius muscles were isolated and homogenized in lysis buffer. IRS1 was immunoprecipitated with anti-IRS1 and subjected to an in vitro kinase assay as described previously (24). Briefly, after extensive washing, IRS1 immunoprecipitates were incubated with L--phosphatidylinositol (2 µg) and [-32P]ATP (5 µCi) for exactly 15 min at room temperature in kinase reaction buffer (10 mM Tris-HCl [pH 7.5], 100 mM NaCl, 14 mM MgCl2, 1.4 mM cold ATP, 1 mM EDTA, 100 µM NaVO4). The reaction was stopped by sequentially adding HCl (8 M) and CHCl3-MeOH (1:1). The lipid products were extracted by centrifugation, spotted on a thin-layer chromatography plate, separated by running buffer (CHCl3-MeOH-H2O-NH4OH at a ratio of 120:94:23.2:4), and visualized by autoradiography.
Transfection. HEK293 cells were transfected with the indicated plasmids by using Lipofectamine 2000 reagents (Invitrogen, Carlsbad, Calif.) according to the manufacturer's instructions. Cells were deprived of serum overnight 24 h after transfection and then treated with 100 nM insulin for 5 or 30 min. Cell extracts were prepared and subjected to immunoprecipitation and immunoblotting with the indicated antibodies as described above.
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RESULTS |
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SH2-B–/– mice were born at the Mendelian frequency (1:2:1 for SH2-B+/+, SH2-B+/–, and SH2-B–/–), suggesting that SH2-B was not required for embryonic development. However, SH2-B–/– homozygotes were smaller than their wild-type littermates during their first 5 weeks of life; the fertility of SH2-B–/– mice was impaired as previously described (26).
Because SH2-B binds to IR (18), we examined whether disruption of SH2-B affects insulin-regulated glucose metabolism. Blood glucose and plasma insulin were continuously monitored in SH2-B knockout and wild-type control littermates. SH2-B–/– knockout mice exhibited normal levels of blood glucose and plasma insulin during their first 8 weeks of life (data not shown); however, as male SH2-B–/– mice aged, they developed hyperglycemia. At 11 weeks of age, blood glucose levels following an overnight 16-h fast increased by 1.56 times in SH2-B–/– males (SH2-B–/–, 102.8 ± 8.9 mg/dl, n = 10; wild type, 65.8 ± 3.9 mg/dl, n = 12). However, SH2-B–/– mice responded normally to intraperitoneally injected glucose during GTT, suggesting that the insulin resistance was relatively mild at this age (data not shown).
Insulin resistance was more severe in older SH2-B–/– males. Blood glucose was elevated more than twofold, and plasma insulin levels were elevated more than eightfold in SH2-B–/– males at an age of 6 to 7 months after a 16-h fast (Fig. 2A and B). Moreover, during a random feeding, insulin levels were 20-fold higher than normal while blood glucose levels were 3.3-fold above those of age-matched wild-type controls (Fig. 2C and D). Female SH2-B–/– mice also developed hyperinsulinemia, but to a lesser extent, and their blood glucose was slightly increased (H. Yang and L. Rui, unpublished data), consistent with various other mouse models in which males are more susceptible to glucose intolerance and type 2 diabetes than females (8, 46).
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cells at the periphery and insulin-producing ß cells at the center, suggesting that SH2-B may not be required for ß cell growth and insulin production (Fig. 4). Hyperplasia of ß cells is a common compensatory mechanism in response to peripheral insulin resistance.
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-32P]ATP. In PBS-treated control mice, basal IR activity was similar between SH2-B–/– and wild-type control mice. Insulin strongly stimulated IR kinase activity in wild-type mice; in contrast, insulin-stimulated IR activity was reduced in SH2-B–/– mice by approximately 38% (Fig. 6B). These results suggest that SH2-B may be a physiological enhancer of IR activation in animals.
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18 h) and then treated with PBS or human insulin. Immunopurified IRS1 or IRS2 was immunoblotted with antiphosphotyrosine antibodies. Insulin-stimulated tyrosine phosphorylation of IRS1 was significantly reduced in muscle from SH2-B–/– mice (Fig. 6C). Quantitative analysis revealed a 70% reduction in skeletal muscle and an 80% reduction in adipose tissues (Fig. 6D). Similarly, insulin-stimulated tyrosine phosphorylation of hepatic IRS2 was reduced by 85% in SH2-B–/– mice (Fig. 6C and D). Interestingly, insulin-stimulated tyrosine phosphorylation of IR, IRS1, and IRS2 was similar between young SH2-B–/– and wild-type littermates at an age of 7 weeks (Fig. 6E), consistent with normal glucose metabolism in young SH2-B knockout mice less than 8 weeks old.
Activation of the PI 3-kinase 
Akt cascade plays an important role in insulin action. The cascade is initiated through the interaction of IRS1 or IRS2 with the p85 regulatory subunit of the PI 3-kinse (44, 45). To determine the interaction of p85 with IRS proteins, mice (7 months) were subjected to fasting overnight and treated with insulin or PBS as a control. IRS1 and IRS2 were immunoprecipitated with anti-IRS1 and anti-IRS2 antibodies, respectively, and immunoblotted with anti-p85 antibody. Insulin promoted coimmunoprecipitation of p85 with both IRS1 and IRS2 in wild-type control mice, whereas these interactions were significantly reduced in SH2-B–/– mice (Fig. 6C). Moreover, IRS1-associated PI 3-kinase activity was measured by in vitro kinase assays. Insulin stimulated the IRS1-associated PI 3-kinase activity by 6-fold in the skeletal muscle from wild-type control animals, whereas PI 3-kinase activity increased only 1.5-fold in response to insulin in SH2-B–/– knockout mice (Fig. 7A). Akt activation was estimated by immunoblotting with anti-phospho-Akt that specifically recognizes phosphorylated Akt at Thr308 or Ser473. Insulin stimulated the phosphorylation of Akt at Thr308 by 5-fold in the liver and 1.5-fold in muscle from wild-type mice, whereas the same treatment increased Thr308 phosphorylation by only 0.6-fold in the liver and 0.1-fold in muscle from SH2-B–/– mice (Fig. 7B). The insulin-stimulated phosphorylation of Akt at Ser473 was also reduced significantly in SH2-B–/– mice (C. Duan and L. Rui, unpublished data). Moreover, the activation of Erk1 and Erk2 was examined by immunoblotting with anti-phospho-MAPK that specifically recognizes phosphorylated and activated Erk1 and Erk2. Insulin rapidly stimulated the activation of Erk1/2 in wild-type control mice, whereas Erk1/2 activation was dramatically reduced in SH2-B–/– mice, although the protein levels of Erk1 and Erk2 were similar between SH2-B–/– and wild-type control mice (Fig. 7C). These data suggest that inhibition of insulin signaling in the liver, muscle, and fat from SH2-B–/– mice, including the activation of IR, IRS1, IRS2, and the PI 3-kinase pathways, may contribute to hyperglycemia, hyperinsulinemia, and glucose intolerance.
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SH2-B could promote IR activation in several ways. Structure data revealed that the SH2 domain of APS, which is 80% identical in amino acid sequence to the SH2 domain of SH2-B, binds as a dimer to the activation loops of both ß subunits of IR (14). SH2-B forms multimers through an N-terminal association domain, suggesting that SH2B may interact with the IR in a similar way (28). Multimeric SH2-B may not only increase its affinity for IR but also stabilize IR in an active state. Alternatively, the binding of SH2-B may protect the activated IR from dephosphorylation by protein tyrosine phosphatases (e.g., PTP1B), prolonging IR activity and signaling.
The late onset of hyperglycemia, hyperinsulinemia, and glucose intolerance in SH2-B knockout mice is intriguing. Increasing evidence suggests that chronic cellular stress, which is associated with aging, impairs insulin signaling, contributing to type 2 diabetes. Stress activates various Ser/Thr kinases including JNK, which may phosphorylate IRS1 and IRS2 at inhibitory serines or threonines (1, 2, 12, 13, 16, 19, 31, 49). In addition, cellular stress also induces a reduction of IRS1 and IRS2 via the ubiquitin/proteasome-mediated degradation, further decreasing insulin sensitivity (34, 37). SH2-B may provide a mechanism to antagonize stress-induced insulin resistance by enhancing IR activation, thus maintaining relatively normal insulin sensitivity during aging and environmental stress. Interestingly, SH2-B is widely expressed in multiple tissues in addition to the liver, muscle, and fat. It has been shown previously that SH2-B binds directly to JAK2 and serves as a substrate of JAK2. JAK2 is a cytoplasmic tyrosine kinase that mediates cell signaling by a verity of cytokines including growth hormone, prolactin, leptin, interleukin-6, and gamma interferon. Cytokines are well characterized to modulate insulin sensitivity. Deletion of SH2-B may also alter the actions of some cytokines, resulting in the inhibition of insulin responses. Therefore, SH2-B may enhance insulin sensitivity both directly by binding to IR and indirectly via modulation of JAK2-mediated cytokine responses.
SH2-B shares homology with APS, especially within the pleckstrin homology and SH2 domains. Both APS and SH2-B bind to the same site in IR and enhance insulin-stimulated activation of Akt1 and Erk1/2 in cultured cells (3, 4, 18, 23, 25, 30). APS binds to Cbl and recruits the Cbl/TC10 pathway in response to insulin (5, 7, 10, 20, 21). The Cbl/TC10 pathway has been reported to be required for insulin-stimulated glucose uptake in adipocytes (7, 10). Surprisingly, disruption of the APS gene increases insulin sensitivity in mice (22). In contrast, deletion of SH2-B induces severe insulin resistance and glucose intolerance, as demonstrated in this study. This striking phenotypic difference indicates that SH2-B cannot be functionally replaced by APS in vivo. A simple explanation would be that SH2-B and APS perform distinct functions in vivo. Alternatively, APS may not be expressed in SH2-B target tissues, or APS expression may not be sufficient to compensate for SH2-B action in SH2-B knockout mice. In contrast, SH2-B may be highly expressed in APS target tissues and may mediate insulin action even better than APS. APS competes for the same binding site in IR with SH2-B. APS also heteromultimerizes with SH2-B (28) and may inhibit SH2-B action. Therefore, deletion of the APS gene may relieve inhibition of SH2-B from APS, resulting in increased insulin sensitivity in APS knockout mice.
In summary, we have shown that disruption of the SH2-B gene impaired insulin signaling in the liver, skeletal muscle, and fat. Consequently, SH2-B knockout mice developed hyperglycemia, hyperinsulinemia, and glucose intolerance during aging. Moreover, SH2-B directly enhanced IR activation and subsequent tyrosine phosphorylation of IRS1 and IRS2 in cultured cells, suggesting that SH2-B is a physiological enhancer of IR activation. SH2-B expression and its regulated signaling events may serve as potential drug targets for therapeutic intervention of insulin resistance and type 2 diabetes.
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ACKNOWLEDGMENTS |
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We thank Decheng Ren and David Morris for assistance.
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FOOTNOTES |
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