Hepatocyte growth factor/scatter factor induces tyrosine phosphorylation of focal adhesion kinase (p125FAK) and promotes migration and invasion by oral squamous cell carcinoma cells.
Fibroblasts or their conditioned medium stimulated invasion by squamous cell carcinoma cells. The fibroblast-derived activity responsible for increased invasion is the hepatocyte growth factor/scatter factor (HGF/SF), a ligand for the c-Met receptor. HGF/SF stimulated migration of the cells on various extracellular matrix substrates but did not alter their adhesion efficiency nor integrin expression. HGF/SF stimulated motility in a two step process: initially cells spread rapidly and formed focal adhesions, and then they disassembled these condensations, which was followed by increased cell locomotion. The focal adhesions contained vinculin, p125FAK, beta 1 integrin, and phosphotyrosine. Within minutes after exposure of cells to HGF/SF, proteins of 125 and 145 kDa showed elevated tyrosine phosphorylation and were identified as p125FAK and c-Met, respectively. Gradual loss of tyrosine phosphorylation coincided with disruption of focal adhesions and conversion to a motile phenotype. HGF/SF-mediated tyrosine phosphorylation of p125FAK was inhibited by the tyrosine kinase inhibitor, herbimycin A, which also blocked spreading and the migratory response. These results indicate that fibroblast-derived HGF/SF triggers migration through the initial recruiting of integrins, cytoskeletal proteins, and p125FAK into focal adhesions that is dependent on tyrosine kinase activity.
Matsumoto
K
K
Department of Anatomy, University of California, San Francisco 94143.
Matsumoto
K
K
Nakamura
T
T
Kramer
R H
RH
D016227:Benzoquinones; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D047029:Lactams, Macrocyclic; D009062:Mouth Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D011809:Quinones / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D016227:Benzoquinones; D015815:Cell Adhesion Molecules; D016023:Integrins; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; D019000:Phosphotyrosine; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human