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Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance

Nature volume 457, pages 1146–1149 (2009)Cite this article

Abstract

Insulin resistance, a hallmark of type 2 diabetes, is a defect of insulin in stimulating insulin receptor signalling1,2, which has become one of the most serious public health threats. Upon stimulation by insulin, insulin receptor recruits and phosphorylates insulin receptor substrate proteins3, leading to activation of the phosphatidylinositol-3-OH kinase (PI(3)K)–Akt pathway. Activated Akt phosphorylates downstream kinases and transcription factors, thus mediating most of the metabolic actions of insulin4,5,6. β-arrestins mediate biological functions of G-protein-coupled receptors by linking activated receptors with distinct sets of accessory and effecter proteins, thereby determining the specificity, efficiency and capacity of signals7,8,9,10,11. Here we show that in diabetic mouse models, β-arrestin-2 is severely downregulated. Knockdown of β-arrestin-2 exacerbates insulin resistance, whereas administration of β-arrestin-2 restores insulin sensitivity in mice. Further investigation reveals that insulin stimulates the formation of a new β-arrestin-2 signal complex, in which β-arrestin-2 scaffolds Akt and Src to insulin receptor. Loss or dysfunction of β-arrestin-2 results in deficiency of this signal complex and disturbance of insulin signalling in vivo, thereby contributing to the development of insulin resistance and progression of type 2 diabetes. Our findings provide new insight into the molecular pathogenesis of insulin resistance, and implicate new preventive and therapeutic strategies against insulin resistance and type 2 diabetes.

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Figure 1: Downregulation of β-arrestin-2 in diabetic mice.
Figure 2: β-arrestin-2 affects the development of insulin resistance.
Figure 3: Insulin stimulated the formation of Receptor/Akt/β-arrestin-2/Src signal complex.
Figure 4: Mutation of β-arrestin-2 contributes to insulin resistance in vivo.

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References

  1. Matthaei, S., Stumvoll, M., Kellerer, M. & Haring, H. U. Pathophysiology and pharmacological treatment of insulin resistance. Endocr. Rev. 21, 585–618 (2000)

    CAS  PubMed  Google Scholar 

  2. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nature Rev. Mol. Cell Biol. 7, 85–96 (2006)

    Article  CAS  Google Scholar 

  3. Sun, X. J. et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 73–77 (1991)

    Article  ADS  CAS  Google Scholar 

  4. Biddinger, S. B. & Kahn, C. R. From mice to men: insights into the insulin resistance syndromes. Annu. Rev. Physiol. 68, 123–158 (2006)

    Article  CAS  Google Scholar 

  5. Franke, T. F. et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81, 727–736 (1995)

    Article  CAS  Google Scholar 

  6. Burgering, B. M. & Coffer, P. J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599–602 (1995)

    Article  ADS  CAS  Google Scholar 

  7. McDonald, P. H. et al. β-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290, 1574–1577 (2000)

    Article  ADS  CAS  Google Scholar 

  8. Luttrell, L. M. et al. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl Acad. Sci. USA 98, 2449–2454 (2001)

    Article  ADS  CAS  Google Scholar 

  9. Luttrell, L. M. et al. β-arrestin-dependent formation of β2 adrenergic receptor-Src protein kinase complexes. Science 283, 655–661 (1999)

    Article  ADS  CAS  Google Scholar 

  10. Beaulieu, J. M. et al. An Akt/β-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122, 261–273 (2005)

    Article  CAS  Google Scholar 

  11. Beaulieu, J. M. et al. A β-arrestin 2 signaling complex mediates lithium action on behavior. Cell 132, 125–136 (2008)

    Article  CAS  Google Scholar 

  12. Yang, Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005)

    Article  ADS  CAS  Google Scholar 

  13. Chen, R. et al. Regulation of Akt/PKB activation by tyrosine phosphorylation. J. Biol. Chem. 276, 31858–31862 (2001)

    Article  CAS  Google Scholar 

  14. Jiang, T. & Qiu, Y. Interaction between Src and a C-terminal proline-rich motif of Akt is required for Akt activation. J. Biol. Chem. 278, 15789–15793 (2003)

    Article  CAS  Google Scholar 

  15. Craxton, A., Jiang, A., Kurosaki, T. & Clark, E. A. Syk and Bruton’s tyrosine kinase are required for B cell antigen receptor-mediated activation of the kinase Akt. J. Biol. Chem. 274, 30644–30650 (1999)

    Article  CAS  Google Scholar 

  16. Wong, B. R. et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol. Cell 4, 1041–1049 (1999)

    Article  CAS  Google Scholar 

  17. Datta, K., Bellacosa, A., Chan, T. O. & Tsichlis, P. N. Akt is a direct target of the phosphatidylinositol 3-kinase. Activation by growth factors, v-src and v-Ha-ras, in Sf9 and mammalian cells. J. Biol. Chem. 271, 30835–30839 (1996)

    Article  CAS  Google Scholar 

  18. DeWire, S. M., Ahn, S., Lefkowitz, R. J. & Shenoy, S. K. β-arrestins and cell signaling. Annu. Rev. Physiol. 69, 483–510 (2007)

    Article  CAS  Google Scholar 

  19. Gao, H. et al. Identification of β-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-κB pathways. Mol. Cell 14, 303–317 (2004)

    Article  CAS  Google Scholar 

  20. Luan, B., Zhang, Z., Wu, Y., Kang, J. & Pei, G. β-arrestin2 functions as a phosphorylation-regulated suppressor of UV-induced NF-κB activation. EMBO J. 24, 4237–4246 (2005)

    Article  CAS  Google Scholar 

  21. Kang, J. et al. A nuclear function of β-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell 123, 833–847 (2005)

    Article  CAS  Google Scholar 

  22. Shi, Y. et al. Critical regulation of CD4+ T cell survival and autoimmunity by β-arrestin 1. Nature Immunol. 8, 817–824 (2007)

    Article  CAS  Google Scholar 

  23. Netea, M. G. et al. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nature Med. 12, 650–656 (2006)

    Article  CAS  Google Scholar 

  24. Arkan, M. C. et al. IKK-β links inflammation to obesity-induced insulin resistance. Nature Med. 11, 191–198 (2005)

    Article  CAS  Google Scholar 

  25. Shen, H. Q., Zhu, J. S. & Baron, A. D. Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse. Metabolism 48, 965–970 (1999)

    Article  CAS  Google Scholar 

  26. Haluzik, M. M. et al. Improvement of insulin sensitivity after peroxisome proliferator-activated receptor-alpha agonist treatment is accompanied by paradoxical increase of circulating resistin levels. Endocrinology 147, 4517–4524 (2006)

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to R. J. Lefkowitz for providing us with β-arr2-KO mice. We thank J.-L. Guan for discussions and comments on the manuscripts. We thank all members of the laboratory for sharing reagents and advice. This research was supported by the Ministry of Science and Technology (2005CB522406, 2006CB943900, 2007CB947904, 2007CB947100, 2007CB948000 and 2009CB941100), National Natural Science Foundation of China (30621091, 30625014, 30623003, 30871285 and 90713047), Shanghai Municipal Commission for Science and Technology (07PJ14099 and 06DZ22032), Chinese Academy of Sciences (KSCX2-YW-R-56 and 2007KIP204).

Author Contributions This study was designed by B.L., J.Z. and G.P. The experiments were performed by B.L., B.D. and G.S. H.W. and W.J. contributed to the hyperinsulinaemic–euglycaemic clamp experiments. X.W. provided type 2 diabetes clinic samples. G.P. supervised the project. B.L. and J.Z. contributed to the writing of the paper. D.L. helped with the manuscript.

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Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, and Graduate School of the Chinese Academy of Sciences,,

    Bing Luan, Jian Zhao, Baoyu Duan, Guangwen Shu, Jiuhong Kang & Gang Pei

  2. Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China ,

    Dangsheng Li

  3. Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People’s Hospital; Shanghai Clinical Center of Diabetes, 200233, Shanghai, China,

    Haiya Wu & Weiping Jia

  4. Shanghai Diabetes Institute,

    Haiya Wu & Weiping Jia

  5. Fudan University Affiliated Zhongshan Hospital, 200032, Shanghai, China ,

    Xiaoying Wang

  6. School of Life Science and Technology, Tongji University, 200092, Shanghai, China ,

    Gang Pei

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  1. Bing Luan
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Correspondence to Gang Pei.

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Luan, B., Zhao, J., Wu, H. et al. Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance. Nature 457, 1146–1149 (2009). https://doi.org/10.1038/nature07617

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