Jf. Lai et al., Involvement of focal adhesion kinase in hepatocyte growth factor-induced scatter of Madin-Darby canine kidney cells, J BIOL CHEM, 275(11), 2000, pp. 7474-7480
Focal adhesion kinase (FAK) has been implicated to play a critical role in
integrin-mediated control of cell behavior. However, it is unclear whether
FAK also participates in the regulation of growth factor-elicited. cellular
functions. In this study, we have demonstrated that although overexpressio
n of FAK in Madin-Dardy canine kidney cells did not alter their growth prop
erty or ability to form tubules within collagen gel upon hepatocyte growth
factor (HGF) stimulation, it apparently enhanced HGF-induced cell scatterin
g This enhancement was largely because of an increase in the third phase (i
.e. cell migration) of cell scattering rather than the first two phases (i.
e. cell spreading and cell-cell dissociation). Conversely, the expression o
f FAR-related nonkinase significantly (similar to 60%) inhibited HGF-induce
d cell migration. Moreover, we have found that the effect of FAK on promoti
ng HGF-induced cell motility was greatly dependent on cell-matrix interacti
ons. We showed that HGF treatment selectively increased the expression of i
ntegrins alpha(2) and, to a lesser extent, alpha(3) in Madin-Dardy canine k
idney cells and that a monoclonal antibody against integrin alpha(2) effici
ently blocked HGF-enhanced cell migration on collagen. In our efforts to de
termine the mechanism. by which FAK promotes HGF-induced cell migration, we
found that FAK mutants deficient in phosphatidylinositol 3-kinase or p130(
Cas) binding failed to promote HGF-induced cell migration, Interestingly, c
ells expressing a FAK mutant defective in Grb2 binding exhibited a rate of
migration similar to 50% lower than that of cells expressing wild type FAK
in response to HGF stimulation, Taken together, our results suggest a link
between HGF-increased integrin expression, FAK activation, and enhanced cel
l motility and implicate a role for FAK in the facilitation of growth facto
r-induced cell motility.