Ga. Van Seventer et al., Focal adhesion kinase regulates beta(1) integrin-dependent T cell migration through an HEF1 effector pathway, EUR J IMMUN, 31(5), 2001, pp. 1417-1427
Although beta (1) integrin-dependent T cell migration is required for immun
e function, little is known of the signaling pathways regulating this migra
tion. We now show that the cytoplasmic tyrosine kinase, focal adhesion kina
se (FAK) plays an essential role in the beta (1) integrin-stimulated migrat
ion of T cells through regulation of the unique Crk-associated substrate (C
as) family docking protein, human enhancer of filamentation 1 (HEF1) and ef
fects on "outside-in" beta (1) integrin signaling. Overexpression of wild-t
ype FAK promoted beta (1) integrin-dependent Jurkat T cell migration, where
as FAK mutated in either its autophosphorylation site or proline rich regio
n 1 (PR1)/HEFI SH3 domain-binding site had a dominant negative effect on mi
gration. In contrast, neither wild-type nor mutant FAK affected Jurkat cell
adhesion to fibronectin, a beta (1) integrin ligand. The migration of FAK-
overexpressing cells directly correlated with the beta (1) integrin-inducib
le tyrosine phosphorylation of endogenous plus wildtype exogenous FAK, and
not with phosphorylation of the FAK-related kinase, Pyk2. FAK was also foun
d to regulate both HEF1-promoted migration, and HEF1 tyrosine phosphorylati
on in beta (1) integrin-stimulated cells, in a manner dependent upon the FA
K autophosphorylation and PR1 sites, and HEF1 SH3 domain. Together, our res
ults indicate that beta (1) integrin-stimulated T cell migration requires a
linear beta (1) integrin-FAK-HEF1 effector pathway.