NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin.
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.
Lehembre
Francois
F
Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland.
Yilmaz
Mahmut
M
Wicki
Andreas
A
Schomber
Tibor
T
Strittmatter
Karin
K
Ziegler
Dominik
D
Kren
Angelika
A
Went
Phillip
P
Derksen
Patrick W B
PW
Berns
Anton
A
Jonkers
Jos
J
Christofori
Gerhard
G
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
D015820:Cadherins; D019006:Neural Cell Adhesion Molecules; D017468:Receptors, Fibroblast Growth Factor; D051076:Proto-Oncogene Proteins c-fyn
Cancer Cell. 2006 Nov;10(5):437-49
17097565
Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10069-74
17537911
Nature. 1998 Mar 12;392(6672):190-3
9515965
Cancer Res. 2006 Feb 15;66(4):2202-9
16489022
J Cell Biol. 2005 Dec 19;171(6):1061-71
16344308
Mol Biol Cell. 2001 Jan;12(1):27-36
11160820
J Cell Biol. 1991 Apr;113(1):173-85
2007622
Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42
16493418
EMBO J. 2007 Jun 20;26(12):2832-42
17541405
J Biol Chem. 2002 Jan 11;277(2):1120-7
11696550
Nat Cell Biol. 2001 Jul;3(7):650-7
11433297
J Cell Biol. 2006 Mar 27;172(7):973-81
16567498
J Cell Sci. 2007 Dec 15;120(Pt 24):4388-94
18042627
Cancer Cell. 2006 Apr;9(4):261-72
16616332
Mol Cell Neurosci. 1996 Aug;8(2/3):99-111
8954625
Nat Rev Cancer. 2004 Feb;4(2):118-32
14964308
Nat Rev Cancer. 2003 May;3(5):362-74
12724734
Curr Opin Investig Drugs. 2004 Dec;5(12):1274-8
15648948
Cell. 1988 Jul 1;54(1):105-15
2898299
J Cell Sci. 2005 Mar 1;118(Pt 5):873-87
15713751
J Cell Biol. 1999 Aug 23;146(4):843-54
10459018
J Biol Chem. 1997 Mar 28;272(13):8310-9
9079653
Nat Med. 1999 Mar;5(3):286-91
10086383
J Cell Biol. 1994 Dec;127(6 Pt 2):2021-36
7806579
J Cell Biol. 2005 Feb 14;168(4):633-42
15716380
Curr Opin Cell Biol. 2003 Dec;15(6):740-6
14644200
Hum Pathol. 2004 Sep;35(9):1148-55
15343518
J Cell Biol. 2002 Apr 29;157(3):521-32
11980923
J Cell Biol. 1999 Jan 25;144(2):325-37
9922458
J Cell Biol. 1989 Jun;108(6):2435-47
2661563
Genes Dev. 1998 Jun 15;12(12):1763-8
9637677
Nature. 1985 May 9-15;315(6015):115-22
2986015
EMBO J. 2003 May 15;22(10):2318-23
12743026