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

Academic Article

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. © 2014 The Authors.
  • Authors

    Published In

  • Cell Reports  Journal
  • Digital Object Identifier (doi)

    Author List

  • Ryu J; Galan AK; Xin X; Dong F; Abdul-Ghani MA; Zhou L; Wang C; Li C; Holmes BM; Sloane LB
  • Start Page

  • 1227
  • End Page

  • 1238
  • Volume

  • 7
  • Issue

  • 4