APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Academic Article uri icon

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.

published proceedings

  • Cell Rep

altmetric score

  • 0.25

author list (cited authors)

  • Ryu, J., Galan, A. K., Xin, X., Dong, F., Abdul-Ghani, M. A., Zhou, L., ... Dong, L. Q.

citation count

  • 107

complete list of authors

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

publication date

  • May 2014