APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor
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Author
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
Liu, Feng
Dong, Lily Q.
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1016/j.celrep.2014.04.006Metadata
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Ryu, 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.Abstract
SUMMARY 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380268/pdf/Terms of Use
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http://nrs.harvard.edu/urn-3:HUL.InstRepos:16120997
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