Ryu, JiyoonGalan, Amanda K.Xin, XiaobanDong, FengAbdul-Ghani, Muhammad A.Zhou, LijunWang, ChanghuaLi, CuilingHolmes, Bekke M.Sloane, Lauren B.Austad, Steven N.Guo, ShaodongMusi, NicolasDeFronzo, Ralph A.Deng, ChuxiaWhite, MorrisLiu, FengDong, Lily Q.2015-06-022014Ryu, J., A. K. Galan, X. Xin, F. Dong, M. A. Abdul-Ghani, L. Zhou, C. Wang, et al. 2014. “APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor.” Cell reports 7 (4): 1227-1238. doi:10.1016/j.celrep.2014.04.006. http://dx.doi.org/10.1016/j.celrep.2014.04.006.2211-1247http://nrs.harvard.edu/urn-3:HUL.InstRepos:16120997SUMMARY 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.en-USJournal Article2015-06-0210.1016/j.celrep.2014.04.006