| First Author | Sieg DJ | Year | 1999 |
| Journal | J Cell Sci | Volume | 112 ( Pt 16) |
| Pages | 2677-91 | PubMed ID | 10413676 |
| Mgi Jnum | J:57324 | Mgi Id | MGI:1344221 |
| Doi | 10.1242/jcs.112.16.2677 | Citation | Sieg DJ, et al. (1999) Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci 112(Pt 16):2677-91 |
| abstractText | FAK localizes to sites of transmembrane integrin receptor clustering and facilitates intracellular signaling events. FAK-null (FAK-) fibroblasts exhibit a rounded morphology, defects in cell migration, and an elevated number of cell-substratum contact sites. Here we show that stable re-expression of epitope-tagged FAK reversed the morphological defects of the FAK- cells through the dynamic regulation of actin structures and focal contact sites in fibronectin (FN) stimulated cells. FAK re-expressing fibroblasts (clones DA2 and DP3) exhibit a characteristic fibrillar shape and display indistinguishable FN receptor-stimulated migration properties compared to normal fibroblasts. Expression of various FAK mutants in the FAK- cells showed that FAK kinase activity, the Tyr-397/SH2 domain binding site, and the first proline-rich SH3 binding region in the FAK C-terminal domain were individually needed to promote full FAK-mediated FAK- cell migration to FN whereas direct paxillin binding to FAK was not required. Expression of the FAK Phe-397 mutant did not promote FAK- cell migration and overexpression of p50(csk) in DA2 cells inhibited migration to FN suggesting that Src-family PTKs play important roles in FAK-mediated motility events. Expression of the FAK C-terminal domain, FRNK, promoted FAK dephosphorylation at Tyr-397 and potently blocked FAK-mediated cell migration. This dominant-negative effect of FRNK was reversed by a point mutation (Leu-1034 to Ser) which prevented FRNK localization to focal contact sites. Our results show that FAK functions as a key regulator of fibronectin receptor stimulated cell migration events through the recruitment of both SH2 and SH3 domain-containing signaling proteins to sites of integrin receptor clustering. |
