HGF induces FAK activation and integrin-mediated adhesion in MTLn3 breast carcinoma cells

Expression of hepatocyte growth factor (HGF) and its tyrosine kinase recept or, c-Met, is positively correlated with breast carcinoma progression, We f ound that in invasive and metastatic MTLn3 breast carcinoma cells, HGF stim ulated both initial adhesion to and motility on the extracellular matrix (E CM) ligands laminin I,type I collagen, and fibronectin. Next, analysis with function-perturbing antibodies showed that adhesion to the different ECM p roteins was mediated through specific pi integrins, In MTLnS cells, HGF ind uced rapid tyrosine phosphorylation and activation of both c-Met and focal adhesion kinase (FAK). Cell anchorage and adhesion to the ECM substrates wa s required for HGF-induced FAK activation, since HGF failed to trigger tyro sine phosphorylation of PAK in suspended cells, Our results provide evidenc e that the 2 signaling pathways, integrin/ECM and c-Met/HGF, cooperate syne rgistically to induce FAK activation in an adhesion-dependent manner, leadi ng to enhanced cell adhesion and motility, Moreover, we found that a FRNK ( the FAK-related non-kinase)-like molecule is expressed in MTLn3 cells. Sinc e FRNK acts as a competitive inhibitor of FAK function, our results suggest that a FRNK-like protein could facilitate disassembly of focal adhesions a nd likely be responsible for the HGF-induced scattering and motility of MTL n3 cells, (C) 1999 Wiley-Liss, Inc.