The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Insulin Resistance* ; Diabetes Mellitus, Type 2*; Mice ; Humans ; Animals ; Phosphorylation ; Serine/metabolism ; Receptor, Insulin/metabolism ; Insulin Receptor Substrate Proteins/genetics ; Insulin Receptor Substrate Proteins/metabolism ; Cell Line ; Phosphoproteins/metabolism ; Insulin/metabolism
    • Abstract:
      Serine phosphorylations on insulin receptor substrate 1 (IRS-1) by diverse kinases aoccur widely during obesity-, stress-, and inflammation-induced conditions in models of insulin resistance and type 2 diabetes. In this study, we define a region within the human IRS-1, which is directly C-terminal to the PTB domain encompassing numerous serine phosphorylation sites including Ser307 (mouse Ser302) and Ser312 (mouse 307) creating a phosphorylation insulin resistance (PIR) domain. We demonstrate that the IRS-1 PTB-PIR with its unphosphorylated serine residues interacts with the insulin receptor (IR) but loses the IR-binding when they are phosphorylated. Surface plasmon resonance studies further confirm that the PTB-PIR binds stronger to IR than just the PTB domain, and that phosphorylations at Ser307, Ser312, Ser315, and Ser323 within the PIR domain result in abrogating the binding. Insulin-responsive cells containing the mutant IRS-1 with all these four serines changed into glutamates to mimic phosphorylations show decreased levels of phosphorylations in IR, IRS-1, and AKT compared to the wild-type IRS-1. Hydrogen-deuterium exchange mass spectrometry experiments indicating the PIR domain interacting with the N-terminal lobe and the hinge regions of the IR kinase domain further suggest the possibility that the IRS-1 PIR domain protects the IR from the PTP1B-mediated dephosphorylation.
      Competing Interests: Competing interests statement:The authors declare no competing interest.
    • References:
      Science. 2004 Oct 15;306(5695):457-61. (PMID: 15486293)
      Science. 1996 Feb 2;271(5249):665-8. (PMID: 8571133)
      J Biol Chem. 2001 Mar 30;276(13):10207-11. (PMID: 11136729)
      Cell. 1996 May 31;85(5):695-705. (PMID: 8646778)
      Sci STKE. 2005 Jan 25;2005(268):pe4. (PMID: 15671481)
      Diabetes. 1999 Jun;48(6):1270-4. (PMID: 10342815)
      J Physiol. 2006 Dec 15;577(Pt 3):997-1007. (PMID: 17008371)
      Mol Cell Biol. 1995 May;15(5):2500-8. (PMID: 7537849)
      J Am Soc Mass Spectrom. 1998 Mar;9(3):225-33. (PMID: 9879360)
      J Biol Chem. 2001 Feb 2;276(5):3543-9. (PMID: 11063744)
      Mol Endocrinol. 2010 Nov;24(11):2179-92. (PMID: 20843941)
      Mol Cell Biol. 1994 Oct;14(10):6433-42. (PMID: 7935368)
      J Biol Chem. 2005 Feb 11;280(6):4422-8. (PMID: 15574412)
      Eur J Clin Invest. 2002 Jun;32 Suppl 3:14-23. (PMID: 12028371)
      Mol Cell. 2008 May 23;30(4):403-14. (PMID: 18498745)
      EMBO J. 1997 Sep 15;16(18):5572-81. (PMID: 9312016)
      EMBO J. 1992 Sep;11(9):3469-79. (PMID: 1380456)
      Structure. 2005 Nov;13(11):1643-51. (PMID: 16271887)
      Curr Opin Struct Biol. 2006 Oct;16(5):561-6. (PMID: 16971114)
      J Biol Chem. 1995 Nov 17;270(46):27407-10. (PMID: 7499194)
      Drug News Perspect. 2004 Sep;17(7):447-53. (PMID: 15514704)
      Metabolism. 1997 Oct;46(10):1140-5. (PMID: 9322796)
      Mol Cell Biol. 2004 Nov;24(21):9668-81. (PMID: 15485932)
      J Biol Chem. 1996 May 31;271(22):13018-22. (PMID: 8662983)
      J Biol Chem. 2004 Jun 11;279(24):25157-63. (PMID: 15069075)
      J Biol Chem. 2002 Nov 1;277(44):42394-8. (PMID: 12228220)
      Diabetes. 2008 Oct;57(10):2644-51. (PMID: 18633112)
      J Clin Invest. 2006 Jul;116(7):1793-801. (PMID: 16823477)
      PLoS One. 2008 Sep 05;3(9):e3151. (PMID: 18773087)
      Nature. 2006 Apr 13;440(7086):944-8. (PMID: 16612386)
      J Endocrinol. 2009 Dec;203(3):337-47. (PMID: 19801385)
      Nature. 2006 Dec 14;444(7121):840-6. (PMID: 17167471)
      Science. 1999 Mar 5;283(5407):1544-8. (PMID: 10066179)
      Diabetes. 1996 Oct;45(10):1379-85. (PMID: 8826975)
      Science. 2009 Jul 17;325(5938):256-60. (PMID: 19608888)
      Cell Metab. 2009 Dec;10(6):491-8. (PMID: 19945406)
      J Biol Chem. 2008 Apr 25;283(17):11226-33. (PMID: 18285345)
      J Clin Invest. 1995 Aug;96(2):801-10. (PMID: 7635975)
      Nature. 2004 Sep 9;431(7005):200-5. (PMID: 15306821)
      Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E581-91. (PMID: 18728222)
      J Biol Chem. 2004 Aug 20;279(34):35298-305. (PMID: 15199052)
      J Biol Chem. 1999 Mar 5;274(10):6114-21. (PMID: 10037694)
      Int J Obes (Lond). 2008 Dec;32 Suppl 7:S52-4. (PMID: 19136991)
      J Cell Biol. 2006 Jun 5;173(5):665-71. (PMID: 16754954)
      J Biol Chem. 1995 Oct 6;270(40):23258-62. (PMID: 7559478)
      J Biol Chem. 2007 Jun 22;282(25):18018-18027. (PMID: 17446166)
    • Grant Information:
      RS-2023-00243435 National Research Foundation of Korea (NRF); 2021R1A6A1A10044154 National Research Foundation of Korea (NRF)
    • Contributed Indexing:
      Keywords: IRS-1; diabetes; insulin receptor; insulin resistance; serine phosphorylation
    • Accession Number:
      452VLY9402 (Serine)
      EC 2.7.10.1 (Receptor, Insulin)
      0 (Insulin Receptor Substrate Proteins)
      0 (Phosphoproteins)
      0 (Insulin)
    • Publication Date:
      Date Created: 20240416 Date Completed: 20240418 Latest Revision: 20240428
    • Publication Date:
      20240428
    • Accession Number:
      PMC11046688
    • Accession Number:
      10.1073/pnas.2401716121
    • Accession Number:
      38625937