Focal adhesion kinase regulates beta1 integrin-dependent T cell migration through an HEF1 effector pathway.
Although beta1 integrin-dependent T cell migration is required for immune function, little is known of the signaling pathways regulating this migration. We now show that the cytoplasmic tyrosine kinase, focal adhesion kinase (FAK) plays an essential role in the beta1 integrin-stimulated migration of T cells through regulation of the unique Crk-associated substrate (Cas) family docking protein, human enhancer of filamentation 1 (HEF1) and effects on "outside-in" beta1 integrin signaling. Overexpression of wild-type FAK promoted beta1 integrin-dependent Jurkat T cell migration, whereas FAK mutated in either its autophosphorylation site or proline rich region 1 (PR1)/HEF1 SH3 domain-binding site had a dominant negative effect on migration. In contrast, neither wild-type nor mutant FAK affected Jurkat cell adhesion to fibronectin, a beta1 integrin ligand. The migration of FAK-overexpressing cells directly correlated with the beta1 integrin-inducible tyrosine phosphorylation of endogenous plus wild-type exogenous FAK, and not with phosphorylation of the FAK-related kinase, Pyk2. FAK was also found to regulate both HEF1-promoted migration, and HEF1 tyrosine phosphorylation in beta1 integrin-stimulated cells, in a manner dependent upon the FAK autophosphorylation and PR1 sites, and HEF1 SH3 domain. Together, our results indicate that beta1 integrin-stimulated T cell migration requires a linear beta1 integrin-FAK-HEF1 effector pathway.
van Seventer
G A
GA
Department of Pathology, University of Chicago, USA.
Salmen
H J
HJ
Law
S F
SF
O'Neill
G M
GM
Mullen
M M
MM
Franz
A M
AM
Kanner
S B
SB
Golemis
E A
EA
van Seventer
J M
JM
D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution / Q000235:genetics; D002448:Cell Adhesion; D002465:Cell Movement; D002999:Clone Cells / Q000201:enzymology / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006367:HeLa Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D019169:Jurkat Cells; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D005353:Fibronectins; D019012:Integrin beta1; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human