APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor

Jiyoon Ryu, Amanda K. Galan, Xiaoban Xin, Feng Dong, Muhammad A. Abdul-Ghani, Lijun Zhou, Changhua Wang, Cuiling Li, Bekke M. Holmes, Lauren B. Sloane, Steven N. Austad, Shaodong Guo, Nicolas Musi, Ralph A. DeFronzo, Chuxia Deng, Morris F. White, Feng Liu, Lily Q. Dong

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Binding of insulin receptor substrate proteins 1 and 2 (IRS1/2) to the insulin receptor (IR) is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction. APPL1 forms a complex with IRS1/2 under basal conditions, and this complex is then recruited to the IR in response to insulin or adiponectin stimulation. The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly reduced in insulin target tissues in obese mice. appl1 deletion in mice consistently leads to systemic insulin resistance and a significant reduction in insulin-stimulated IRS1/2, but not IR, tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a site downstream of the IR. Our study uncovers a mechanism regulating insulin signaling and crosstalk between the insulin and adiponectin pathways.

Original languageEnglish (US)
Pages (from-to)1227-1238
Number of pages12
JournalCell Reports
Volume7
Issue number4
DOIs
StatePublished - May 22 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ryu, J., Galan, A. K., Xin, X., Dong, F., Abdul-Ghani, M. A., Zhou, L., Wang, C., Li, C., Holmes, B. M., Sloane, L. B., Austad, S. N., Guo, S., Musi, N., DeFronzo, R. A., Deng, C., White, M. F., Liu, F., & Dong, L. Q. (2014). APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Reports, 7(4), 1227-1238. https://doi.org/10.1016/j.celrep.2014.04.006