Abstract
Focal adhesion kinase (FAK) has been implicated to be a point of convergence of integrin and growth factor signaling pathways. Here we report that FAK directly interacts with the hepatocyte growth factor receptor c-Met. Phosphorylation of c-Met at Tyr-1349 and, to a lesser extent, Tyr-1356 is required for its interaction with the band 4.1 and ezrin/radixin/moesin homology domain (FERM domain) of FAK. The F2 subdomain of the FAK FERM domain alone is sufficient for Met binding, in which a patch of basic residues (216KAKTLRK222) are critical for the interaction. Met-FAK interaction leads to FAK activation and subsequent contribution to hepatocyte growth factor-induced cell motility and cell invasion. Our results provide evidence that constitutive Met-FAK interaction may be a critical determinant for tumor cells to acquire invasive potential.
Supplemental material for this article may be found at http://mcb.asm.org/.
We thank D. Ilic for FAK-null MEF, T. Hirano for Gab1-null MEF, P. Soriano for SYF cells, P.-C. Yang for lung cancer cell lines, J.-L. Guan for recombinant baculoviruses, G. Vande Woude for c-Met cDNA, P. M. Comoglio and M. Park for the Tpr-Met constructs, J. T. Parsons for FAK cDNA, and W.-M. Yang for the pcDNA3.1-HA vector. We are grateful to P.-C. Chan, C.-M. Chen, and T.-H. Chen for assistance with plasmid construction and to Y.-C. Li for purification of the histidine-tagged FAK NH2 domain.
This work was supported by grants NSC-93-2311-B-005-012, NSC-94-2320-B005-003, NSC95-3112-B005-001, and TCVGH-NCHU947610 to H.-C.C.