c-Src-mediated epithelial cell migration and invasion regulated by PDZ binding site.
c-Src tyrosine kinase controls proliferation, cell adhesion, and cell migration and is highly regulated. A novel regulatory mechanism to control c-Src function that has recently been identified involves the C-terminal amino acid sequence Gly-Glu-Asn-Leu (GENL) of c-Src as ligand for PDZ domains. Herein, we determined the biological relevance of this c-Src regulation in human breast epithelial cells. The intact GENL sequence maintained c-Src in an inactive state in starved cells and restricted c-Src functions that might lead to metastatic transformation under normal growth conditions. c-Src with a C-terminal Leu/Ala mutation in GENL (Src-A) promoted the activation and translocation of cortactin and focal adhesion kinase and increased the motility and persistence of cell migration on the basement membrane. Src-A promoted increased extracellular proteolytic activity, and in acinar cultures, it led to the escape of cells through the basement membrane into the surrounding matrix. We ascribe the regulatory function of C-terminal Leu to the role of GENL in modulating c-Src activity downstream of cell matrix adhesion. We propose that the C terminus of c-Src via its GENL sequence presents a mechanism that restricts c-Src in epithelia and prevents progression toward an invasive phenotype.
Baumgartner
Martin
M
Institute of Medical Virology, University of Zürich, Gloriastrasse 30, CH-8006 Zürich, Switzerland. Martin.Baumgartner@immv.uzh.ch
Radziwill
Gerald
G
Lorger
Mihaela
M
Weiss
Andreas
A
Moelling
Karin
K
D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D016764:Cell Polarity; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008024:Ligands; D009361:Neoplasm Invasiveness; D054731:PDZ Domains; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
D015820:Cadherins; D008024:Ligands; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)