Required role of focal adhesion kinase (FAK) for integrin-stimulated cellmigration

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1999
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Sieg, David J.
Schlaepfer, David D.
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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 receptorstimulated 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 p50csk 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 FAKmediated 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 domaincontaining signaling proteins to sites of integrin receptor clustering.

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Fachgebiet (DDC)
570 Biowissenschaften, Biologie
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FAK, Fibronectin, Cell migration, Signaling
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ISO 690SIEG, David J., Christof R. HAUCK, David D. SCHLAEPFER, 1999. Required role of focal adhesion kinase (FAK) for integrin-stimulated cellmigration. In: Journal of Cell Science. 1999, 112, pp. 2677-2691
BibTex
@article{Sieg1999Requi-8080,
  year={1999},
  title={Required role of focal adhesion kinase (FAK) for integrin-stimulated cellmigration},
  volume={112},
  journal={Journal of Cell Science},
  pages={2677--2691},
  author={Sieg, David J. and Hauck, Christof R. and Schlaepfer, David D.}
}
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