title: NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin.
abstract: Loss of expression of the cell-cell adhesion molecule E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) in development and in the progression from epithelial tumours to invasive and metastatic cancers. Here, we demonstrate that the loss of E-cadherin function upregulates expression of the neuronal cell adhesion molecule (NCAM). Subsequently, a subset of NCAM translocates from fibroblast growth factor receptor (FGFR) complexes outside lipid rafts into lipid rafts where it stimulates the non-receptor tyrosine kinase p59(Fyn) leading to the phosphorylation and activation of focal adhesion kinase and the assembly of integrin-mediated focal adhesions. Ablation of NCAM expression during EMT inhibits focal adhesion assembly, cell spreading and EMT. Conversely, forced expression of NCAM induces epithelial cell delamination and migration, and high NCAM expression correlates with tumour invasion. These results establish a mechanistic link between the loss of E-cadherin expression, NCAM function, focal adhesion assembly and cell migration and invasion.
authors.affiliation: Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Lehembre
authors.forename: Mahmut
authors.initials: M
authors.lastname: Yilmaz
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.forename: Tibor
authors.initials: T
authors.lastname: Schomber
authors.forename: Karin
authors.initials: K
authors.lastname: Strittmatter
authors.forename: Dominik
authors.initials: D
authors.lastname: Ziegler
authors.forename: Angelika
authors.initials: A
authors.lastname: Kren
authors.forename: Phillip
authors.initials: P
authors.lastname: Went
authors.forename: Patrick W B
authors.initials: PW
authors.lastname: Derksen
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004848:Epithelium / Q000502:physiology; D022001:Focal Adhesions / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism
chemical_list: D015820:Cadherins; D019006:Neural Cell Adhesion Molecules; D017468:Receptors, Fibroblast Growth Factor; D051076:Proto-Oncogene Proteins c-fyn
references.citation: Cancer Cell. 2006 Nov;10(5):437-49
references.pmid: 17097565
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10069-74
references.pmid: 17537911
references.citation: Nature. 1998 Mar 12;392(6672):190-3
references.pmid: 9515965
references.citation: Cancer Res. 2006 Feb 15;66(4):2202-9
references.pmid: 16489022
references.citation: J Cell Biol. 2005 Dec 19;171(6):1061-71
references.pmid: 16344308
references.citation: Mol Biol Cell. 2001 Jan;12(1):27-36
references.pmid: 11160820
references.citation: J Cell Biol. 1991 Apr;113(1):173-85
references.pmid: 2007622
references.citation: Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42
references.pmid: 16493418
references.citation: EMBO J. 2007 Jun 20;26(12):2832-42
references.pmid: 17541405
references.citation: J Biol Chem. 2002 Jan 11;277(2):1120-7
references.pmid: 11696550
references.citation: Nat Cell Biol. 2001 Jul;3(7):650-7
references.pmid: 11433297
references.citation: J Cell Biol. 2006 Mar 27;172(7):973-81
references.pmid: 16567498
references.citation: J Cell Sci. 2007 Dec 15;120(Pt 24):4388-94
references.pmid: 18042627
references.citation: Cancer Cell. 2006 Apr;9(4):261-72
references.pmid: 16616332
references.citation: Mol Cell Neurosci. 1996 Aug;8(2/3):99-111
references.pmid: 8954625
references.citation: Nat Rev Cancer. 2004 Feb;4(2):118-32
references.pmid: 14964308
references.citation: Nat Rev Cancer. 2003 May;3(5):362-74
references.pmid: 12724734
references.citation: Curr Opin Investig Drugs. 2004 Dec;5(12):1274-8
references.pmid: 15648948
references.citation: Cell. 1988 Jul 1;54(1):105-15
references.pmid: 2898299
references.citation: J Cell Sci. 2005 Mar 1;118(Pt 5):873-87
references.pmid: 15713751
references.citation: J Cell Biol. 1999 Aug 23;146(4):843-54
references.pmid: 10459018
references.citation: J Biol Chem. 1997 Mar 28;272(13):8310-9
references.pmid: 9079653
references.citation: Nat Med. 1999 Mar;5(3):286-91
references.pmid: 10086383
references.citation: J Cell Biol. 1994 Dec;127(6 Pt 2):2021-36
references.pmid: 7806579
references.citation: J Cell Biol. 2005 Feb 14;168(4):633-42
references.pmid: 15716380
references.citation: Curr Opin Cell Biol. 2003 Dec;15(6):740-6
references.pmid: 14644200
references.citation: Hum Pathol. 2004 Sep;35(9):1148-55
references.pmid: 15343518
references.citation: J Cell Biol. 2002 Apr 29;157(3):521-32
references.pmid: 11980923
references.citation: J Cell Biol. 1999 Jan 25;144(2):325-37
references.pmid: 9922458
references.citation: J Cell Biol. 1989 Jun;108(6):2435-47
references.pmid: 2661563
references.citation: Genes Dev. 1998 Jun 15;12(12):1763-8
references.pmid: 9637677
references.citation: Nature. 1985 May 9-15;315(6015):115-22
references.pmid: 2986015
references.citation: EMBO J. 2003 May 15;22(10):2318-23
references.pmid: 12743026