ArticleBiophysical journal2015
Allosteric regulation of focal adhesion kinase by PIP₂ and ATP.
Article in Biophysical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
- Article
- The Influence of Phosphoinositide Lipids in the Molecular Biology of Membrane Proteins: Recent Insights from Simulations.Journal of molecular biology · 2025Review
- Kinesin-1 mediates proper ER folding of the CaEMBO reports · 2024Article
- Polarized focal adhesion kinase activity within a focal adhesion during cell migration.Nature chemical biology · 2023Article
- Three-Dimensional-QSAR and Relative Binding Affinity Estimation of Focal Adhesion Kinase Inhibitors.Molecules (Basel, Switzerland) · 2023Article
- Article
- Interplay between mechanics and signalling in regulating cell fate.Nature reviews. Molecular cell biology · 2022Review
- Niban apoptosis regulator 1 promotes gemcitabine resistance by activating the focal adhesion kinase signaling pathway in bladder cancer.Journal of Cancer · 2022Article
- FAK inhibitors as promising anticancer targets: present and future directions.Future medicinal chemistry · 2021Review
- A regulatory role of membrane by direct modulation of the catalytic kinase domain.Small GTPases · 2021Review
- ZINC40099027 activates human focal adhesion kinase by accelerating the enzymatic activity of the FAK kinase domain.Pharmacology research & perspectives · 2021Article
- Review of PIP2 in Cellular Signaling, Functions and Diseases.International journal of molecular sciences · 2020Review
- Transforming growth factor β (TGF-β) receptor signaling regulates kinase networks and phosphatidylinositol metabolism during T-cell activation.The Journal of biological chemistry · 2020Article
- Characterization of Lipid-Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation.Chemical reviews · 2019Review
- T cells transduce T-cell receptor signal strength by generating different phosphatidylinositols.The Journal of biological chemistry · 2019Article
- MARCKS Is Necessary for Netrin-DCC Signaling and Corpus Callosum Formation.Molecular neurobiology · 2018Article
- Revisiting Netrin-1: One Who Guides (Axons).Frontiers in cellular neuroscience · 2018Review
- Article
- Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane.Scientific reports · 2016Article
- Phosphatidylinositol 4,5-Bisphosphate Modulates the Affinity of Talin-1 for Phospholipid Bilayers and Activates Its Autoinhibited Form.Biochemistry · 2016Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that regulates cell signaling, proliferation, migration, and development. A major mechanism of regulation of FAK activity is an intramolecular autoinhibitory interaction between two of its domains--the catalytic and FERM domains. Upon cell adhesion to the extracellular matrix, FAK is being translocated toward focal adhesion sites and activated. Interactions of FAK with phosphoinositide phosphatidylinsositol-4,5-bis-phosphate (PIP₂) are required to activate FAK. However, the molecular mechanism of the activation remains poorly understood. Recent fluorescence resonance energy transfer experiments revealed a closure of the FERM-kinase interface upon ATP binding, which is reversed upon additional binding of PIP₂. Here, we addressed the allosteric regulation of FAK by performing all-atom molecular-dynamics simulations of a FAK fragment containing the catalytic and FERM domains, and comparing the dynamics in the absence or presence of ATP and PIP₂. As a major conformational change, we observe a closing and opening motion upon ATP and additional PIP₂ binding, respectively, in good agreement with the fluorescence resonance energy transfer experiments. To reveal how the binding of the regulatory PIP₂ to the FERM F2 lobe is transduced to the very distant F1/N-lobe interface, we employed force distribution analysis. We identified a network of mainly charged residue-residue interactions spanning from the PIP₂ binding site to the distant interface between the kinase and FERM domains, comprising candidate residues for mutagenesis to validate the predicted mechanism of FAK activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.