APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor

• APPL1 facilitates IRS1/2 binding to the insulin receptor
• APPL1 function is stimulated by insulin/adiponectin-induced phosphorylation
• Knockout of APPL1 impairs insulin and adiponectin signaling and function in mice
• Adiponectin is a sensitizer (but not a mimic) of insulin in muscle cells and in vivo

SummaryBinding 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.

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