title: Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance.
abstract: IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.
authors.affiliation: 1] Key Laboratory of Systems Biomedicine (Ministry of Education) of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025, China [2] Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China.
authors.forename: Li-Yu
authors.initials: LY
authors.lastname: Huang
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Bao-Feng
authors.initials: BF
authors.lastname: Wei
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Ji-Qiu
authors.initials: JQ
authors.lastname: Wang
authors.forename: Bing-Hao
authors.initials: BH
authors.lastname: Wu
authors.forename: Zhuang-Zhuang
authors.initials: ZZ
authors.lastname: Zhang
authors.forename: Ying-Yong
authors.initials: YY
authors.lastname: Hou
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Sun
authors.forename: Ren-Ming
authors.initials: RM
authors.lastname: Hu
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.forename: Ze-Guang
authors.initials: ZG
authors.lastname: Han
mesh_terms: D000818:Animals; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency*; D011972:Receptor, Insulin / Q000378:metabolism*
chemical_list: D008840:Microfilament Proteins; D011972:Receptor, Insulin
references.citation: J Neurosci. 2009 Feb 4;29(5):1586-95
references.pmid: 19193906
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6
references.pmid: 8790415
references.citation: Biochem J. 2011 May 15;436(1):45-52
references.pmid: 21401524
references.citation: Endocrinology. 2011 Apr;152(4):1284-9
references.pmid: 21239437
references.citation: Eur J Cell Biol. 2008 Sep;87(8-9):699-708
references.pmid: 18417251
references.citation: J Biol Chem. 1996 Feb 9;271(6):2921-8
references.pmid: 8621681
references.citation: Semin Cell Dev Biol. 2010 Jun;21(4):340-9
references.pmid: 19963073
references.citation: Nat Rev Endocrinol. 2009 Oct;5(10):553-8
references.pmid: 19687788
references.citation: Mol Microbiol. 2010 Jan;75(2):308-23
references.pmid: 19889090
references.citation: Sci Prog. 2008;91(Pt 3):285-316
references.pmid: 18853578
references.citation: Front Biosci (Schol Ed). 2011 Jan 01;3:621-31
references.pmid: 21196400
references.citation: Nature. 2001 Dec 13;414(6865):799-806
references.pmid: 11742412
references.citation: Trends Cell Biol. 2008 Feb;18(2):52-60
references.pmid: 18215522
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21743-8
references.pmid: 21098279
references.citation: J Physiol Biochem. 2009 Mar;65(1):1-9
references.pmid: 19588726
references.citation: PLoS One. 2011;6(8):e23571
references.pmid: 21887275
references.citation: J Cell Sci. 2007 May 1;120(Pt 9):1663-72
references.pmid: 17430976
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6754-9
references.pmid: 19366662
references.citation: Nature. 2010 Oct 21;467(7318):963-6
references.pmid: 20962845
references.citation: Am J Physiol Endocrinol Metab. 2002 Dec;283(6):E1135-43
references.pmid: 12424102
references.citation: Annu Rev Physiol. 2006;68:123-58
references.pmid: 16460269
references.citation: Cell Mol Life Sci. 2007 Apr;64(7-8):873-91
references.pmid: 17347799
references.citation: Curr Biol. 2009 Jan 27;19(2):95-107
references.pmid: 19150238
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9543-8
references.pmid: 10931946
references.citation: BMC Biol. 2009 Jul 10;7:38
references.pmid: 19589179
references.citation: Cardiorenal Med. 2012 Aug;2(3):200-210
references.pmid: 22969776
references.citation: Diabetes. 2009 Dec;58(12):2718-25
references.pmid: 19940235
references.citation: Semin Cell Dev Biol. 2010 Jun;21(4):350-6
references.pmid: 19913105
references.citation: J Biol Chem. 2009 Apr 3;284(14):9225-36
references.pmid: 19208628
references.citation: Nat Rev Endocrinol. 2009 Jul;5(7):401-8
references.pmid: 19488075
references.citation: Curr Opin Cell Biol. 2011 Feb;23(1):14-21
references.pmid: 21093245