Phosphorylation of RIAM by src promotes integrin activation by unmasking the PH domain of RIAM.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101087697 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-4186 (Electronic) Linking ISSN: 09692126 NLM ISO Abbreviation: Structure Subsets: MEDLINE
    • Publication Information:
      Publication: 2000- : Cambridge, Mass. : Cell Press
      Original Publication: London : Current Biology, c1993-
    • Subject Terms:
      Adaptor Proteins, Signal Transducing/*chemistry ; Membrane Proteins/*chemistry ; src-Family Kinases/*metabolism; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Binding Sites ; CHO Cells ; Cell Membrane/metabolism ; Cricetinae ; Cricetulus ; HEK293 Cells ; Humans ; Integrins/chemistry ; Integrins/metabolism ; Jurkat Cells ; Membrane Proteins/metabolism ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Phosphorylation ; Protein Binding ; Protein Transport
    • Abstract:
      Integrin activation controls cell adhesion, migration, invasion, and extracellular matrix remodeling. RIAM (RAP1-GTP-interacting adaptor molecule) is recruited by activated RAP1 to the plasma membrane (PM) to mediate integrin activation via an inside-out signaling pathway. This process requires the association of the pleckstrin homology (PH) domain of RIAM with the membrane PIP2. We identify a conserved intermolecular interface that masks the PIP2-binding site in the PH domains of RIAM. Our data indicate that phosphorylation of RIAM by Src family kinases disrupts this PH-mediated interface, unmasks the membrane PIP2-binding site, and promotes integrin activation. We further demonstrate that this process requires phosphorylation of Tyr267 and Tyr427 in the RIAM PH domain by Src. Our data reveal an unorthodox regulatory mechanism of small GTPase effector proteins by phosphorylation-dependent PM association of the PH domain and provide new insights into the link between Src kinases and integrin signaling.
      Competing Interests: Declaration of interests The authors declare no competing interests.
      (Copyright © 2020 Elsevier Ltd. All rights reserved.)
    • Comments:
      Comment in: Structure. 2021 Apr 1;29(4):305-307. (PMID: 33798425)
    • References:
      Blood. 2016 Jul 28;128(4):479-87. (PMID: 27207789)
      J Biol Chem. 2012 Jun 15;287(25):20823-9. (PMID: 22549881)
      PLoS One. 2015 Nov 23;10(11):e0143423. (PMID: 26600301)
      J Exp Med. 1999 May 3;189(9):1467-78. (PMID: 10224287)
      PLoS One. 2010 Jan 26;5(1):e8899. (PMID: 20126650)
      Dev Cell. 2004 Oct;7(4):585-95. (PMID: 15469846)
      Nat Commun. 2014 Dec 18;5:5880. (PMID: 25520155)
      J Mol Cell Biol. 2014 Apr;6(2):128-39. (PMID: 24287201)
      Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8378-83. (PMID: 10411883)
      J Cell Sci. 1995 Nov;108 ( Pt 11):3635-44. (PMID: 8586674)
      Biochem Biophys Res Commun. 2004 Dec 24;325(4):1443-8. (PMID: 15555589)
      Front Med. 2014 Mar;8(1):6-16. (PMID: 24477625)
      Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55. (PMID: 15299926)
      Immunol Rev. 2007 Aug;218:114-25. (PMID: 17624948)
      Nat Rev Immunol. 2015 Nov;15(11):692-704. (PMID: 26471775)
      Blood. 2015 Dec 17;126(25):2695-703. (PMID: 26324702)
      Nat Commun. 2015 Sep 30;6:8492. (PMID: 26419705)
      Nat Struct Mol Biol. 2009 Aug;16(8):833-9. (PMID: 19648926)
      Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3524-3529. (PMID: 30733287)
      Growth Factors. 2005 Sep;23(3):193-201. (PMID: 16243711)
      J Exp Med. 1996 Apr 1;183(4):1415-26. (PMID: 8666900)
      J Cell Sci. 2017 Aug 1;130(15):2435-2446. (PMID: 28701514)
      Cell Tissue Res. 2010 Jan;339(1):269-80. (PMID: 19693543)
      Structure. 2016 May 3;24(5):721-729. (PMID: 27150043)
      Oncogene. 2004 Oct 18;23(48):7990-8000. (PMID: 15489916)
      Nat Cell Biol. 2019 Jan;21(1):25-31. (PMID: 30602766)
      Sci Signal. 2009 Dec 01;2(99):ra79. (PMID: 19952372)
      J Cell Biol. 2012 Oct 15;199(2):317-30. (PMID: 23045549)
      Structure. 2014 Dec 2;22(12):1810-1820. (PMID: 25465129)
      Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32. (PMID: 15572765)
      Nucleic Acids Res. 2011 Jan;39(Database issue):D761-70. (PMID: 21036862)
      Nat Rev Drug Discov. 2016 Mar;15(3):173-83. (PMID: 26822833)
      Blood. 2015 Dec 17;126(25):2704-12. (PMID: 26337492)
      Curr Opin Cell Biol. 2005 Oct;17(5):509-16. (PMID: 16099636)
      J Biol Chem. 2009 Feb 20;284(8):5119-27. (PMID: 19098287)
      Annu Rev Cell Dev Biol. 2003;19:541-64. (PMID: 14570581)
      World J Gastroenterol. 2018 May 7;24(17):1868-1880. (PMID: 29740202)
      J Cell Biol. 1994 May;125(3):639-49. (PMID: 7513706)
      Mol Cell Biol. 2006 Nov;26(22):8655-65. (PMID: 16966372)
    • Grant Information:
      P30 GM124166 United States GM NIGMS NIH HHS; R35 GM119560 United States GM NIGMS NIH HHS; R01 CA211670 United States CA NCI NIH HHS; P30 CA006927 United States CA NCI NIH HHS; T32 CA009035 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: FYN; LCK; PH domain; PIP2 binding; RAP1; RIAM; Src kinase; integrin signaling; lamellipodin; phosphorylation
    • Accession Number:
      0 (APBB1IP protein, human)
      0 (Adaptor Proteins, Signal Transducing)
      0 (Integrins)
      0 (Membrane Proteins)
      0 (Phosphatidylinositol 4,5-Diphosphate)
      EC 2.7.10.2 (src-Family Kinases)
    • Publication Date:
      Date Created: 20201204 Date Completed: 20211123 Latest Revision: 20220402
    • Publication Date:
      20221213
    • Accession Number:
      PMC8026550
    • Accession Number:
      10.1016/j.str.2020.11.011
    • Accession Number:
      33275877