title: α-Catenin phosphorylation promotes intercellular adhesion through a dual-kinase mechanism.
abstract: The cadherin-catenin adhesion complex is a key contributor to epithelial tissue stability and dynamic cell movements during development and tissue renewal. How this complex is regulated to accomplish these functions is not fully understood. We identified several phosphorylation sites in mammalian αE-catenin (also known as catenin α-1) and Drosophila α-Catenin within a flexible linker located between the middle (M)-region and the carboxy-terminal actin-binding domain. We show that this phospho-linker (P-linker) is the main phosphorylated region of α-catenin in cells and is sequentially modified at casein kinase 2 and 1 consensus sites. In Drosophila, the P-linker is required for normal α-catenin function during development and collective cell migration, although no obvious defects were found in cadherin-catenin complex assembly or adherens junction formation. In mammalian cells, non-phosphorylatable forms of α-catenin showed defects in intercellular adhesion using a mechanical dispersion assay. Epithelial sheets expressing phosphomimetic forms of α-catenin showed faster and more coordinated migrations after scratch wounding. These findings suggest that phosphorylation and dephosphorylation of the α-catenin P-linker are required for normal cadherin-catenin complex function in Drosophila and mammalian cells.
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA The Driskill Graduate Training Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: David J
authors: DJ
authors: Escobar
authors: Department of Cell and Systems Biology, University of Toronto, Toronto, ON, M5S 3G5 Canada.
authors: Ridhdhi
authors: R
authors: Desai
authors: University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5T 2M9, Canada.
authors: Noboru
authors: N
authors: Ishiyama
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA The Driskill Graduate Training Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Stephen S
authors: SS
authors: Folmsbee
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA The Driskill Graduate Training Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Megan N
authors: MN
authors: Novak
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Annette S
authors: AS
authors: Flozak
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA The Driskill Graduate Training Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Rebecca L
authors: RL
authors: Daugherty
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Rigen
authors: R
authors: Mo
authors: Department of Chemistry of Life Processes, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Dhaval
authors: D
authors: Nanavati
authors: Department of Cell and Systems Biology, University of Toronto, Toronto, ON, M5S 3G5 Canada.
authors: Ritu
authors: R
authors: Sarpal
authors: Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana, IL 61801, USA.
authors: Deborah
authors: D
authors: Leckband
authors: University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5T 2M9, Canada.
authors: Mitsu
authors: M
authors: Ikura
authors: Department of Cell and Systems Biology, University of Toronto, Toronto, ON, M5S 3G5 Canada u.tepass@utoronto.ca c-gottardi@northwestern.edu.
authors: Ulrich
authors: U
authors: Tepass
authors: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA Department of Cellular and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA u.tepass@utoronto.ca c-gottardi@northwestern.edu.
authors: Cara J
authors: CJ
authors: Gottardi
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D061985:Madin Darby Canine Kidney Cells; D008969:Molecular Sequence Data; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D051178:alpha Catenin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D015820:Cadherins; D051178:alpha Catenin; D047389:Casein Kinase I; D047390:Casein Kinase II
keywords: Adhesion; Migration; Phospho-regulation; α-catenin
references: J Cell Biol. 2000 Jan 10;148(1):189-202
references: 10629228
references: Cell. 2010 Dec 23;143(7):1174-89
references: 21183079
references: EMBO J. 2001 Jul 16;20(14):3645-56
references: 11447106
references: J Biol Chem. 2002 May 24;277(21):18868-74
references: 11907041
references: J Clin Invest. 2004 Mar;113(6):885-94
references: 15067321
references: Mol Cell Biol. 2004 May;24(10):4184-95
references: 15121840
references: Genetics. 2004 Apr;166(4):1775-82
references: 15126397
references: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12130-5
references: 15302935
references: Nat Rev Mol Cell Biol. 2004 Aug;5(8):614-25
references: 15366705
references: Development. 1993 Jun;118(2):629-40
references: 8223282
references: Biochem Biophys Res Commun. 1994 Feb 15;198(3):898-905
references: 8117294
references: Cell Adhes Commun. 1994 Aug;2(4):319-27
references: 7820535
references: Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9220-5
references: 9256463
references: J Cell Biol. 1998 Apr 6;141(1):297-308
references: 9531567
references: J Cell Biol. 1998 May 4;141(3):755-64
references: 9566974
references: J Biol Chem. 1998 Oct 23;273(43):28314-21
references: 9774455
references: Eur J Biochem. 1999 Mar;260(2):520-6
references: 10095790
references: Neuron. 1999 Mar;22(3):451-61
references: 10197526
references: J Cell Biol. 1999 Feb 8;144(3):533-47
references: 9971747
references: Mol Cell Proteomics. 2004 Nov;3(11):1093-101
references: 15345747
references: Development. 2005 Aug;132(15):3493-504
references: 16014514
references: Cell. 2005 Dec 2;123(5):903-15
references: 16325583
references: Science. 2006 Mar 17;311(5767):1609-12
references: 16543460
references: Cell. 2006 Nov 3;127(3):635-48
references: 17081983
references: Oncogene. 2006 Nov 16;25(54):7166-79
references: 16767162
references: Mol Cell Biol. 2007 May;27(10):3804-16
references: 17353278
references: Mol Biol Cell. 2007 Nov;18(11):4261-78
references: 17699590
references: J Proteome Res. 2008 Apr;7(4):1675-82
references: 18327897
references: J Proteome Res. 2011 Dec 2;10(12):5354-62
references: 22073976
references: Nat Cell Biol. 2013 Mar;15(3):261-73
references: 23417122
references: J Cell Biol. 2013 Apr 1;201(1):131-43
references: 23547031
references: J Biol Chem. 2013 May 31;288(22):15913-25
references: 23589308
references: Development. 2013 Jul;140(13):2808-17
references: 23720044
references: Mol Biol Cell. 2013 Dec;24(23):3710-20
references: 24068324
references: Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5260-5
references: 24706864
references: J Cell Sci. 2014 Apr 15;127(Pt 8):1779-91
references: 24522187
references: Nat Commun. 2014;5:4525
references: 25077739
references: Mol Biol Cell. 2014 Aug 15;25(16):2365-74
references: 24966173
references: Science. 2014 Oct 31;346(6209):1254211
references: 25359979
references: J Cell Sci. 2012 Jan 1;125(Pt 1):233-45
references: 22266901
references: J Biol Chem. 1999 Dec 17;274(51):36734-40
references: 10593980
references: Int Rev Cell Mol Biol. 2012;293:45-83
references: 22251558
references: Dev Cell. 2012 Feb 14;22(2):309-19
references: 22340496
references: Proc Natl Acad Sci U S A. 2012 May 29;109(22):8576-81
references: 22586082
references: Nat Rev Mol Cell Biol. 2012 Oct;13(10):631-45
references: 23000794
references: Nat Struct Mol Biol. 2013 Feb;20(2):188-93
references: 23292143
references: Inflamm Bowel Dis. 2011 Mar;17(3):831-48
references: 21319274
references: Gut. 2011 Sep;60(9):1204-12
references: 21307168
references: J Cell Biol. 2011 Nov 14;195(4):543-52
references: 22084304
references: Curr Biol. 2008 Apr 8;18(7):532-7
references: 18394891
references: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7
references: 18669648
references: Nat Cell Biol. 2008 Sep;10(9):1027-38
references: 19160483
references: J Biol Chem. 2009 Jan 30;284(5):2880-90
references: 19047047
references: Curr Top Dev Biol. 2009;89:33-54
references: 19737641
references: Mol Cell. 2009 Nov 25;36(4):547-59
references: 19941816
references: J Cell Biol. 2010 Apr 19;189(2):339-52
references: 20404114
references: PLoS One. 2010;5(4):e10184
references: 20419129
references: Nat Cell Biol. 2010 Jun;12(6):533-42
references: 20453849
references: Nat Rev Mol Cell Biol. 2010 Jul;11(7):502-14
references: 20571587
references: J Cell Biol. 2010 Jun 28;189(7):1107-15
references: 20584916
references: Cell. 2001 Feb 23;104(4):605-17
references: 11239416