HGF induces FAK activation and integrin-mediated adhesion in MTLn3 breast carcinoma cells.
Expression of hepatocyte growth factor (HGF) and its tyrosine kinase receptor, c-Met, is positively correlated with breast carcinoma progression. We found that in invasive and metastatic MTLn3 breast carcinoma cells, HGF stimulated both initial adhesion to and motility on the extracellular matrix (ECM) ligands laminin 1, type I collagen, and fibronectin. Next, analysis with function-perturbing antibodies showed that adhesion to the different ECM proteins was mediated through specific beta1 integrins. In MTLn3 cells, HGF induced rapid tyrosine phosphorylation and activation of both c-Met and focal adhesion kinase (FAK). Cell anchorage and adhesion to the ECM substrates was required for HGF-induced FAK activation, since HGF failed to trigger tyrosine phosphorylation of FAK in suspended cells. Our results provide evidence that the 2 signaling pathways, integrin/ECM and c-Met/HGF, cooperate synergistically to induce FAK activation in an adhesion-dependent manner, leading to enhanced cell adhesion and motility. Moreover, we found that a FRNK (the FAK-related non-kinase)-like molecule is expressed in MTLn3 cells. Since FRNK acts as a competitive inhibitor of FAK function, our results suggest that a FRNK-like protein could facilitate disassembly of focal adhesions and likely be responsible for the HGF-induced scattering and motility of MTLn3 cells.
Beviglia
L
L
Department of Stomatology, University of California, San Francisco, San Francisco, CA, USA.
Kramer
R H
RH
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000187:drug effects* / Q000378:metabolism; D002465:Cell Movement; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D016326:Extracellular Matrix Proteins; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D016023:Integrins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D007797:Laminin; D015674:Mammary Neoplasms, Animal / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
D000906:Antibodies; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D016023:Integrins; D007797:Laminin; D009363:Neoplasm Proteins; C121346:laminin 1; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat