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Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):E3177-86. doi: 10.1073/pnas.1317022111. Epub 2014 Jul 21.

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes.

Author information

Structural Biology and Biocomputing Program and.
BBVA Foundation Cancer Cell Biology Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain;
Heidelberg Institute for Theoretical Studies, 69118 Heidelberg, Germany;
Immunology and Oncology Department, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain;
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; and.
Institute of Structural and Molecular Biology andDepartment of Chemistry, University College London, London WC1H 0AJ, United Kingdom.
Structural Biology and Biocomputing Program and


Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase (NRTK) with key roles in integrating growth and cell matrix adhesion signals, and FAK is a major driver of invasion and metastasis in cancer. Cell adhesion via integrin receptors is well known to trigger FAK signaling, and many of the players involved are known; however, mechanistically, FAK activation is not understood. Here, using a multidisciplinary approach, including biochemical, biophysical, structural, computational, and cell biology approaches, we provide a detailed view of a multistep activation mechanism of FAK initiated by phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Interestingly, the mechanism differs from canonical NRTK activation and is tailored to the dual catalytic and scaffolding function of FAK. We find PI(4,5)P2 induces clustering of FAK on the lipid bilayer by binding a basic region in the regulatory 4.1, ezrin, radixin, moesin homology (FERM) domain. In these clusters, PI(4,5)P2 induces a partially open FAK conformation where the autophosphorylation site is exposed, facilitating efficient autophosphorylation and subsequent Src recruitment. However, PI(4,5)P2 does not release autoinhibitory interactions; rather, Src phosphorylation of the activation loop in FAK results in release of the FERM/kinase tether and full catalytic activation. We propose that PI(4,5)P2 and its generation in focal adhesions by the enzyme phosphatidylinositol 4-phosphate 5-kinase type Iγ are important in linking integrin signaling to FAK activation.


cell signaling; phosphoinositides

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