title: APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor.
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.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Jiyoon
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Galan
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Xiaoban
authors.initials: X
authors.lastname: Xin
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Dong
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Abdul-Ghani
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Changhua
authors.initials: C
authors.lastname: Wang
authors.affiliation: Mammalian Genetics Section, GDDB, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Bekke M
authors.initials: BM
authors.lastname: Holmes
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Sloane
authors.affiliation: 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.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Austad
authors.affiliation: Division of Molecular Cardiology, Texas A&M University, Temple, TX 76504, USA.
authors.forename: Shaodong
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
authors.affiliation: Mammalian Genetics Section, GDDB, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.affiliation: Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Dong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; C510733:Appl1 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D011972:Receptor, Insulin