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Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

Oncogene volume 30, pages 153–166 (2011)Cite this article

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Abstract

Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. In contrast, substitution of Tyr194 with Glu (Y194E substitution) leads to constitutive activation of FAK. The phosphorylation of FAK on Tyr194 may cause conformational changes in the FERM domain, which disrupts the intramolecular inhibitory interaction between the FERM and kinase domains of FAK. Moreover, substitution of the basic residues in the 216KAKTLRK222 patch in the FERM domain with Ala antagonizes the effect of the Y194E substitution on FAK activation, thus suggesting that the interactions between the phosphorylated Tyr194 and the basic resides in the 216KAKTLRK222 patch may allow FAK to be activated through relief of its autoinhibition. Collectively, this study provides the first example to explain how FAK is activated by receptor tyrosine kinases.

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Acknowledgements

This work is supported by Grants NSC97-3112-B-005-001 and NSC97-2628-B-005-001-MY3 from the National Science Council, Taiwan and NHRI-EX97-9730BI from the National Health Research Institutes, Taiwan.

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Authors and Affiliations

  1. Department of Life Science, National Chung Hsing University, Taichung, Taiwan

    T-H Chen, C-L Chen & H-C Chen

  2. Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan

    P-C Chan & H-C Chen

  3. Department of Nutrition, China Medical University, Taichung, Taiwan

    H-C Chen

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Correspondence to H-C Chen.

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Chen, TH., Chan, PC., Chen, CL. et al. Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition. Oncogene 30, 153–166 (2011). https://doi.org/10.1038/onc.2010.398

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