Co-operative effect of c-Src and ezrin in deregulation of cell-cell contacts and scattering of mammary carcinoma cells.
The non-receptor tyrosine kinase c-Src is activated in many human cancer types, and induces deregulation of cadherin-based cell-cell contacts and actin cytoskeleton. Because ezrin, a protein which cross-links the plasma membrane with the actin cytoskeleton, is often over-expressed in human cancers, and participates in cell adhesion, motility, and cell scattering, we therefore investigated whether c-Src co-operates with ezrin in regulating cell-cell contacts in a murine mammary carcinoma cell line, SP1. SP1 cells over-expressing wild type ezrin, or an activated c-Src mutant, formed loose aggregates which scattered spontaneously when plated on plastic. When wild type ezrin and activated c-Src were co-expressed, scattering was increased, cell-cell contacts disrupted, and cell aggregation prevented. Pre-treatment with the c-Src family kinase inhibitor PP2 partially restored aggregation of cells expressing activated c-Src and wild type ezrin, indicating that c-Src family kinases act co-operatively with ezrin in regulating cell-cell contacts. Furthermore, expression of a truncated NH2-terminal domain of ezrin, which has dominant negative function, blocked the cell scattering effect of activated c-Src and promoted formation of cohesive cell-cell contacts. Together, these results suggest co-operativity between c-Src and ezrin in deregulation of cell-cell contacts and enhancing scattering of mammary carcinoma cells.
Elliott
Bruce E
BE
Queen's University Cancer Research Institute, Division of Cancer Biology and Genetics, Queen's University, Kingston, ON, Canada K7L 3N6. elliottb@post.queensu.ca
Qiao
Hui
H
Louvard
Daniel
D
Arpin
Monique
M
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion; D002449:Cell Aggregation; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D003598:Cytoskeletal Proteins; D005260:Female; D005353:Fibronectins / Q000737:chemistry; D047468:Immunoprecipitation; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010969:Plastics / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases; D000099149:Ezrin
D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D010750:Phosphoproteins; D010969:Plastics; D011505:Protein-Tyrosine Kinases; D014443:Tyrosine; D019061:src-Family Kinases; D000099149:Ezrin; C000631346:CSK protein, human