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Cell Rep. 2014 May 22;7(4):1227-38. doi: 10.1016/j.celrep.2014.04.006. Epub 2014 May 10.

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

Author information

1
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
2
Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
3
Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
4
Mammalian Genetics Section, GDDB, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
5
Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
6
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA; The Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
7
Division of Molecular Cardiology, Texas A&M University, Temple, TX 76504, USA.
8
Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA; The Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
10
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA; The Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA. Electronic address: dongQ@uthscsa.edu.

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.

PMID:
24813896
PMCID:
PMC4380268
DOI:
10.1016/j.celrep.2014.04.006
[Indexed for MEDLINE]
Free PMC Article

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