Crk synergizes with epidermal growth factor for epithelial invasion and morphogenesis and is required for the met morphogenic program.
Activation of the Met receptor tyrosine kinase through its ligand, hepatocyte growth factor, stimulates cell spreading, cell dispersal, and the inherent morphogenic program of various epithelial cell lines. Although both hepatocyte growth factor and epidermal growth factor (EGF) can activate downstream signaling pathways in Madin-Darby canine kidney epithelial cells, EGF fails to promote the breakdown of cell-cell junctional complexes and initiate an invasive morphogenic program. We have undertaken a strategy to identify signals that synergize with EGF in this process. We provide evidence that the overexpression of the CrkII adapter protein complements EGF-stimulated pathways to induce cell dispersal in two-dimensional cultures and cell invasion and branching morphogenesis in three-dimensional collagen gels. This finding correlates with the ability of CrkII to promote the breakdown of adherens junctions in stable cell lines and the ability of EGF to stimulate enhanced Rac activity in cells overexpressing CrkII. We have previously shown that the Gab1-docking protein is required for branching morphogenesis downstream of the Met receptor. Consistent with a role for CrkII in promoting EGF-dependent branching morphogenesis, the binding of Gab1 to CrkII is required for the branching morphogenic program downstream of Met. Together, our data support a role for the CrkII adapter protein in epithelial invasion and morphogenesis and underscores the importance of considering the synergistic actions of signaling pathways in cancer progression.
Departments of Biochemistry, Medicine, and Oncology, Molecular Oncology Group, McGill University Hospital Center, McGill University, Montreal, Quebec H3A 1A1, Canada.
Louie
L
Lamorte
Sonia
S
Rodrigues
Monica
M
Naujokas
Morag
M
Park
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003094:Collagen / Q000378:metabolism*; D004285:Dogs; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D019084:Fluorescent Antibody Technique, Indirect; D018257:Helix-Loop-Helix Motifs; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D007668:Kidney; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009024:Morphogenesis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D018909:src Homology Domains
D003094:Collagen; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins; D015534:Trans-Activators