Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling.
Although Src expression and activity are often elevated in colon cancer, the precise consequences of overexpression of the non-catalytic Src homology (SH) domains, or enhanced catalytic activity, are unknown. We show that, in KM12C colon cancer cells, elevated Src activity causes the components of adherens junctions, including vinculin, to be redistributed to Src-induced integrin adhesion complexes. Specifically, elevated Src activity blocks proper assembly of cell cell contacts after cells are switched from media containing a low level of calcium to media containing a high level of calcium, and E-cadherin remains internalized. In contrast, although elevated expression of the non-catalytic domains of Src is sufficient to induce assembly of integrin adhesion complexes, it does not induce disorganization of E-cadherin-associated intercellular contacts. Surprisingly, Src-induced disruption of E-cadherin localization requires specific integrin signalling, because E-cadherin redistribution is blocked by loss of cell-matrix interaction, or by inhibitory antibodies to alpha(v) or beta(1) integrin subunits. Furthermore, phosphorylation of the integrin-regulated focal adhesion kinase (FAK) on Src-specific sites is required for Src-induced de-regulation of E-cadherin, demonstrating interdependence between integrin-induced signals and cadherin-associated adhesion changes induced by Src.
The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Bearsden, Glasgow G61 1BD, UK.
Egle
E
Avizienyte
Anne W
AW
Wyke
Robert J
RJ
Jones
Gordon W
GW
McLean
M Andrew
MA
Westhoff
Valerie G
VG
Brunton
Margaret C
MC
Frame
D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D003110:Colonic Neoplasms / Q000378:metabolism*; D006801:Humans; D039421:Integrin alpha2; D039564:Integrin alphaV; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D000906:Antibodies; D015703:Antigens, CD; D015820:Cadherins; D039421:Integrin alpha2; D039564:Integrin alphaV; D019012:Integrin beta1; D016023:Integrins; D011994:Recombinant Proteins; D016392:Proto-Oncogene Proteins pp60(c-src)