A switch from p130Cas/Crk to Gab1/Crk signaling correlates with anchorage independent growth and JNK activation in cells transformed by the Met receptor oncoprotein.
Cell transformation is associated with anchorage independent growth and morphological changes characterized by reduced adhesion and spreading. The molecular signals that control these events are poorly understood. The Met receptor tyrosine kinase is deregulated in human tumors and an oncogenic derivative of this receptor transforms cells. In this paper we ... demonstrate that fibroblasts transformed by the Met oncoprotein display decreased cell spreading consistent with the loss of actin stress fibers and vinculin staining focal adhesions. In contrast to control cells, focal adhesion kinase, p130Cas and paxillin are weakly or not detectably tyrosine phosphorylated in Met transformed cells. Moreover, although paxillin and p130Cas associate with the Crk adapter protein in control cells, they fail to associate with Crk in Met transformed cells, yet these cells are motile and capable of wound closure to the same extent as control cells. In Met transformed cells, Crk predominantly associates with the Cbl and Gab1docking proteins in a tyrosine phosphorylation dependent manner. The coupling of Gab1, but not Cbl, with Crk is retained in cells grown in suspension and enhances JNK activation. We propose that the loss of adhesion dependent signals required for cell cycle progression is compensated through Met induced Gab1/Crk signals.
Mesh Terms:
3T3 Cells, Actins, Animals, Cell Adhesion, Cell Division, Cell Size, Cell Transformation, Neoplastic, Crk-Associated Substrate Protein, Cytoskeletal Proteins, Enzyme Activation, Fibronectins, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesions, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice, Mitogen-Activated Protein Kinase Kinases, Mutation, Oncogene Proteins, Paxillin, Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Binding, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-crk, Proto-Oncogene Proteins c-met, Retinoblastoma-Like Protein p130, Signal Transduction, Stress Fibers, Wound Healing
3T3 Cells, Actins, Animals, Cell Adhesion, Cell Division, Cell Size, Cell Transformation, Neoplastic, Crk-Associated Substrate Protein, Cytoskeletal Proteins, Enzyme Activation, Fibronectins, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesions, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice, Mitogen-Activated Protein Kinase Kinases, Mutation, Oncogene Proteins, Paxillin, Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Binding, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-crk, Proto-Oncogene Proteins c-met, Retinoblastoma-Like Protein p130, Signal Transduction, Stress Fibers, Wound Healing
Oncogene
Date: Dec. 07, 2000
PubMed ID: 11146548
View in: Pubmed Google Scholar
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