title: Vinculin regulates the recruitment and release of core focal adhesion proteins in a force-dependent manner.
abstract: BACKGROUND
  Cells sense the extracellular environment using adhesion receptors (integrins) linked to the intracellular actin cytoskeleton through a complex network of regulatory proteins that, all together, form focal adhesions (FAs). The molecular basis of how these sensing units are regulated, how they are implicated in transducing mechanical stimuli, and how this leads to a spatiotemporal coordination of FAs is unclear.
  
  
  RESULTS
  Here we show that vinculin, through its links to the talin-integrin complex and F-actin, regulates the transmission of mechanical signals from the extracellular matrix to the actomyosin machinery. We demonstrate that the vinculin interaction with the talin-integrin complex drives the recruitment and release of core FA components. The activation state of vinculin is itself regulated by force, as underscored by our observation that vinculin localization to FAs is dependent on actomyosin contraction. Using a variety of vinculin mutants, we establish which components of the cell-matrix adhesion network are coordinated through direct and indirect associations with vinculin. Moreover, using cyclic stretching, we demonstrate that vinculin plays a key role in the transmission of extracellular mechanical stimuli leading to the reorganization of cell polarity. Of particular importance is the actin-binding tail region of vinculin, without which the cell's ability to repolarize in response to cyclic stretching is perturbed.
  
  
  CONCLUSIONS
  Overall our data promote a model whereby vinculin controls the transmission of intracellular and extracellular mechanical cues that are important for the spatiotemporal assembly, disassembly, and reorganization of FAs to coordinate polarized cell motility.
authors: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, England, UK.
authors: Alex
authors: A
authors: Carisey
authors: Ricky
authors: R
authors: Tsang
authors: Alexandra M
authors: AM
authors: Greiner
authors: Nadja
authors: N
authors: Nijenhuis
authors: Nikki
authors: N
authors: Heath
authors: Alicja
authors: A
authors: Nazgiewicz
authors: Ralf
authors: R
authors: Kemkemer
authors: Brian
authors: B
authors: Derby
authors: Joachim
authors: J
authors: Spatz
authors: Christoph
authors: C
authors: Ballestrem
mesh_terms: D000199:Actins / Q000378:metabolism; D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D016764:Cell Polarity; D021982:Cell-Matrix Junctions / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D008545:Melanoma; D051379:Mice; D009154:Mutation; D012516:Osteosarcoma; D011485:Protein Binding; D016608:Talin / Q000378:metabolism; D016596:Vinculin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D016023:Integrins; D016608:Talin; D016596:Vinculin; D000205:Actomyosin
references: J Cell Biol. 2011 Oct 31;195(3):499-513
references: 22042621
references: Mol Cell Biol. 2002 Sep;22(18):6582-91
references: 12192056
references: J Cell Sci. 2001 Oct;114(Pt 20):3583-90
references: 11707510
references: Nature. 2006 Apr 20;440(7087):1069-72
references: 16547516
references: Biochem J. 1996 Sep 15;318 ( Pt 3):753-7
references: 8836115
references: Cell. 2002 Sep 20;110(6):673-87
references: 12297042
references: Nat Cell Biol. 2007 Aug;9(8):858-67
references: 17671451
references: Nature. 2010 Nov 25;468(7323):580-4
references: 21107430
references: J Biol Chem. 2005 Apr 29;280(17):17109-17
references: 15728584
references: J Cell Biol. 2010 Mar 22;188(6):891-903
references: 20231384
references: Eur J Cell Biol. 2011 Feb-Mar;90(2-3):157-63
references: 20655620
references: J Cell Sci. 2009 Oct 15;122(Pt 20):3644-51
references: 19812308
references: J Cell Sci. 1998 Jun;111 ( Pt 12):1649-58
references: 9601095
references: Nat Cell Biol. 2008 Sep;10(9):1062-8
references: 19160486
references: J Cell Biol. 2001 Dec 24;155(7):1319-32
references: 11756480
references: J Biol Chem. 2006 Dec 29;281(52):40389-98
references: 17074767
references: J Cell Sci. 2003 Nov 15;116(Pt 22):4605-13
references: 14576354
references: Mol Biol Cell. 2000 Sep;11(9):2999-3012
references: 10982396
references: Nat Rev Mol Cell Biol. 2001 Nov;2(11):793-805
references: 11715046
references: Nat Cell Biol. 2001 May;3(5):466-72
references: 11331874
references: J Cell Biol. 2005 May 9;169(3):459-70
references: 15883197
references: Nat Rev Mol Cell Biol. 2006 Jan;7(1):20-31
references: 16493410
references: Am J Pathol. 2004 Sep;165(3):1033-44
references: 15331426
references: Nature. 2004 Jul 29;430(6999):583-6
references: 15195105
references: J Cell Biol. 2010 Mar 22;188(6):877-90
references: 20308429
references: PLoS One. 2012;7(5):e37990
references: 22629471
references: Cell. 1992 Aug 7;70(3):401-10
references: 1643658
references: J Cell Sci. 1994 Feb;107 ( Pt 2):709-17
references: 8207093
references: J Cell Biol. 2007 Dec 3;179(5):1043-57
references: 18056416
references: EMBO J. 2006 Nov 15;25(22):5284-93
references: 17082770
references: J Cell Sci. 1996 Nov;109 ( Pt 11):2715-26
references: 8937989
references: Dev Cell. 2010 Sep 14;19(3):365-76
references: 20833360
references: Eur J Cell Biol. 2006 Jun;85(6):487-500
references: 16584805
references: Nature. 2010 Jul 8;466(7303):263-6
references: 20613844
references: J Biol Chem. 2006 Mar 17;281(11):7228-36
references: 16407299
references: Science. 2009 Jan 30;323(5914):638-41
references: 19179532
references: J Biol Chem. 2010 Sep 17;285(38):29577-87
references: 20610383
references: Biomaterials. 2011 Mar;32(8):2043-51
references: 21163521
references: J Biol Chem. 1994 Apr 29;269(17):12611-9
references: 8175670
references: J Cell Biol. 2002 Dec 9;159(5):881-91
references: 12473693
references: Biochem Soc Trans. 2004 Jun;32(Pt3):434-7
references: 15157154
references: J Cell Biol. 1999 Jan 11;144(1):59-69
references: 9885244
references: J Biol Chem. 2006 Jun 9;281(23):16006-15
references: 16608855
references: Biochem Soc Trans. 1991 Nov;19(4):1065-9
references: 1794463
references: J Cell Biol. 2001 May 14;153(4):881-8
references: 11352946
references: Trends Cell Biol. 2006 Sep;16(9):453-60
references: 16893648
references: Curr Opin Cell Biol. 2001 Oct;13(5):584-92
references: 11544027
references: J Cell Biol. 2010 Jun 28;189(7):1107-15
references: 20584916