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FAK integrates growth-factor and integrin signals to promote cell migration

Nature Cell Biology volume 2, pages 249–256 (2000)Cite this article

Abstract

Here we show that cells lacking focal adhesion kinase (FAK) are refractory to motility signals from platelet-derived and epidermal growth factors (PDGF and EGF respectively), and that stable re-expression of FAK rescues these defects. FAK associates with activated PDGF- and EGF-receptor (PDGFR and EGFR) signalling complexes, and expression of the band-4.1-like domain at the FAK amino terminus is sufficient to mediate an interaction with activated EGFR. However, efficient EGF-stimulated cell migration also requires FAK to be targeted, by its carboxy-terminal domain, to sites of integrin-receptor clustering. Although the kinase activity of FAK is not needed to promote PDGF- or EGF-stimulated cell motility, kinase-inactive FAK is transphosphorylated at the indispensable Src-kinase-binding site, FAK Y397, after EGF stimulation of cells. Our results establish that FAK is an important receptor-proximal link between growth-factor-receptor and integrin signalling pathways.

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Figure 1: FAK forms a complex with the activated PDGFR and is required for PDGF-stimulated cell motility.
Figure 2: The FAK SH2-binding site and Src-family protein-tyrosine-kinase activity are necessary for PDGF-stimulated cell migration.
Figure 3: FAK forms a complex with the activated EGFR and is required for EGF-stimulated cell motility.
Figure 4: The FAK N-terminal domain is required for association with EGFR and EGF-stimulated cell motility.
Figure 5: Exogenously expressed FAK N-terminal domain can form a complex with activated EGFR.
Figure 6: Expression of the FAK C-terminal domain inhibits the FAK–EGFR association and EGF-stimulated cell motility.
Figure 7: Model of FAK function.

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Acknowledgements

We thank A. Moore and S. Reider for assistance, M. Schwartz for polyclonal antiserum directed to β1 integrins, T. Hunter for the PDGFR-β-expression vector and polyclonal antibodies to the PDGFRβ, B. Mayer for the pEBG mammalian GST-fusion expression vector and J.-L. Guan for the HA-tagged FAK(ΔC14) expression vector. This work was supported by National Cancer Institute, American Cancer Society and American Heart Association grants to D.D.S. D.J.S was supported by an NIH postdoctoral training grant; C.R.H by the Deutsche Forschungsgemeinschaft (HA-2856/1-1); D.I. by the UCSF Academic Senate; and C.H.D by the American Heart Association.

Correspondence and requests for materials should be addressed to D.D.S.

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Author notes

  1. David J. Sieg, Christof R. Hauck and Erik Schaefer: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Immunology, IMM 26, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California, 92037, USA

    David J. Sieg, Christof R. Hauck, Candice K. Klingbeil & David D. Schlaepfer

  2. Department of Stomatology, University of California San Francisco, San Francisco, California, 94143, USA

    Dusko Ilic & Caroline H. Damsky

  3. QCB-A Division of BioSource International, Hopkinton, Massachusetts, 01748, USA

    Erik Schaefer

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Correspondence to David D. Schlaepfer.

Supplementary information

Figure S1

Comparisons of the expression levels of FAK, Pyk2, EGF receptor (EGFR), PDGF receptor (PDGFR) and p130 Cas in FAK+/+, FAK-/- and DA2 cells. All cells are p53-/-. (PDF 71 kb)

Figure S2 In vivo recruitment of FAK to apical attachment sites of beads coated with fibronectin (FN), EGF or fibronectin and EGF (FN+EGF) in DA2 and FAK+/+ fibroblasts.

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Sieg, D., Hauck, C., Ilic, D. et al. FAK integrates growth-factor and integrin signals to promote cell migration . Nat Cell Biol 2, 249–256 (2000). https://doi.org/10.1038/35010517

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