Pleckstrin Homology (PH) Domain Leucine-rich Repeat Protein Phosphatase Controls Cell Polarity by Negatively Regulating the Activity of Atypical Protein Kinase C.

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  • Author(s): Xiong X;Xiong X; Li X; Li X; Wen YA; Wen YA; Gao T; Gao T; Gao T
  • Source:
    The Journal of biological chemistry [J Biol Chem] 2016 Nov 25; Vol. 291 (48), pp. 25167-25178. Date of Electronic Publication: 2016 Oct 19.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
      Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
    • Subject Terms:
      Cell Polarity/*physiology ; Isoenzymes/*metabolism ; Nuclear Proteins/*metabolism ; Phosphoprotein Phosphatases/*metabolism ; Protein Kinase C/*metabolism ; Protein Kinase C-epsilon/*metabolism; Adaptor Proteins, Signal Transducing ; Animals ; Caco-2 Cells ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Membrane/enzymology ; Cell Membrane/genetics ; Humans ; Isoenzymes/genetics ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Nuclear Proteins/genetics ; Phosphoprotein Phosphatases/genetics ; Protein Kinase C/genetics ; Protein Kinase C-epsilon/genetics
    • Abstract:
      The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures as indicated by the formation of aberrant multi-lumen structures. Overexpression of PHLPP resulted in a decrease in aPKC phosphorylation at both the activation loop and the turn motif sites; conversely, knockdown of PHLPP increased aPKC phosphorylation. Moreover, in vitro dephosphorylation experiments revealed that both aPKC isoforms were substrates of PHLPP. Interestingly, knockdown of PKCζ, but not PKCι, led to similar disruption of the polarized lumen structure, suggesting that PKCζ likely controls the polarization process of Caco2 cells. Furthermore, knockdown of PHLPP altered the apical membrane localization of aPKCs and reduced the formation of aPKC-Par3 complex. Taken together, our results identify a novel role of PHLPP in regulating aPKC and cell polarity.
      (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
    • References:
      Curr Biol. 1998 Sep 24;8(19):1069-77. (PMID: 9768361)
      Mol Cell. 2005 Apr 1;18(1):13-24. (PMID: 15808505)
      Curr Opin Cell Biol. 2005 Oct;17(5):548-58. (PMID: 16098727)
      Exp Cell Res. 2013 Jun 10;319(10):1357-64. (PMID: 23535009)
      Gastroenterology. 2012 Feb;142(2):377-87.e1-5. (PMID: 22044669)
      EMBO Rep. 2011 Jun 24;12(8):818-24. (PMID: 21701506)
      Mol Cell Biol. 2011 Dec;31(24):4917-27. (PMID: 21986499)
      Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12519-24. (PMID: 16116079)
      Trends Cell Biol. 2004 Jun;14(6):312-9. (PMID: 15183188)
      Biochim Biophys Acta. 2015 Oct;1852(10 Pt A):2013-23. (PMID: 26187040)
      Mol Cell. 2010 May 28;38(4):512-23. (PMID: 20513427)
      Biochem J. 2003 Mar 1;370(Pt 2):361-71. (PMID: 12495431)
      Semin Cell Biol. 1992 Jun;3(3):149-55. (PMID: 1623204)
      Genes Cells. 2002 Nov;7(11):1161-71. (PMID: 12390250)
      Cell Death Differ. 2011 Sep;18(9):1470-7. (PMID: 21617693)
      J Cell Biol. 2012 Jul 23;198(2):185-94. (PMID: 22826122)
      Biochim Biophys Acta. 2008 Mar;1778(3):614-30. (PMID: 18005931)
      Semin Cell Dev Biol. 2000 Aug;11(4):291-9. (PMID: 10966863)
      J Cell Biol. 2004 Feb 16;164(4):603-12. (PMID: 14769856)
      Nat Cell Biol. 2007 Sep;9(9):1016-24. (PMID: 17762893)
      Hepatology. 2014 Oct;60(4):1251-63. (PMID: 24825302)
      Mol Cell. 2007 Mar 23;25(6):917-31. (PMID: 17386267)
      J Biol Chem. 2008 Mar 7;283(10):6300-11. (PMID: 18162466)
      Nat Rev Cancer. 2012 May 24;12(6):387-400. (PMID: 22622641)
      J Cell Sci. 2009 May 15;122(Pt 10):1595-606. (PMID: 19401335)
      Gastroenterology. 2014 May;146(5):1301-12.e1-10. (PMID: 24530606)
      Trends Endocrinol Metab. 2008 Aug;19(6):223-30. (PMID: 18511290)
      J Cell Physiol. 2011 Apr;226(4):879-87. (PMID: 20945390)
      Cold Spring Harb Perspect Biol. 2012 Jun 01;4(6):null. (PMID: 22553378)
      EMBO Rep. 2014 Feb;15(2):191-8. (PMID: 24375676)
      Carcinogenesis. 2014 Feb;35(2):396-406. (PMID: 24072773)
      J Biol Chem. 2014 Sep 5;289(36):25021-30. (PMID: 25035426)
      Cancer Cell. 2011 Aug 16;20(2):173-86. (PMID: 21840483)
      Mol Cell Biol. 2004 Oct;24(19):8778-89. (PMID: 15367694)
      Oncogene. 2005 Nov 14;24(50):7493-501. (PMID: 16288296)
      Oncogene. 2008 Nov 24;27(55):6970-80. (PMID: 19029938)
      J Biochem. 2003 Jan;133(1):9-16. (PMID: 12761193)
      J Biol Chem. 2011 Apr 8;286(14):12461-74. (PMID: 21300793)
      Methods. 2003 Jul;30(3):256-68. (PMID: 12798140)
      FEBS J. 2013 Jan;280(2):572-83. (PMID: 22340730)
      Oncogene. 2009 Feb 19;28(7):994-1004. (PMID: 19079341)
      Acta Crystallogr D Biol Crystallogr. 2010 May;66(Pt 5):577-83. (PMID: 20445233)
      J Cell Biol. 2008 Nov 17;183(4):625-33. (PMID: 19001128)
      Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1642-7. (PMID: 20080691)
      Mol Cell Biol. 2013 Nov;33(22):4594-605. (PMID: 24061475)
      Cancer Res. 2013 Sep 1;73(17 ):5402-15. (PMID: 23856247)
      Cell. 2010 Apr 30;141(3):509-23. (PMID: 20434988)
      Nat Cell Biol. 2006 Nov;8(11):1235-45. (PMID: 17060907)
      Nat Rev Cancer. 2011 Dec 15;12(1):23-38. (PMID: 22169974)
    • Grant Information:
      P30 CA177558 United States CA NCI NIH HHS; R01 CA133429 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: Akt PKB; PHLPP; atypical PKC; cell polarity; dephosphorylation; phosphatase; protein kinase C (PKC); protein phosphorylation
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Cell Adhesion Molecules)
      0 (Cell Cycle Proteins)
      0 (Isoenzymes)
      0 (Membrane Proteins)
      0 (Nuclear Proteins)
      0 (PARD3 protein, human)
      0 (Pard3 protein, mouse)
      EC 2.7.1.- (Prkce protein, mouse)
      EC 2.7.11.13 (PRKCE protein, human)
      EC 2.7.11.13 (Protein Kinase C)
      EC 2.7.11.13 (Protein Kinase C-epsilon)
      EC 2.7.11.13 (protein kinase C lambda)
      EC 3.1.3.16 (PHLPP1 protein, human)
      EC 3.1.3.16 (PHLPP1 protein, mouse)
      EC 3.1.3.16 (PHLPP2 protein, human)
      EC 3.1.3.16 (Phosphoprotein Phosphatases)
    • Publication Date:
      Date Created: 20161021 Date Completed: 20170526 Latest Revision: 20210209
    • Publication Date:
      20221213
    • Accession Number:
      PMC5122783
    • Accession Number:
      10.1074/jbc.M116.740639
    • Accession Number:
      27760826