Mechanism of Focal Adhesion Kinase Mechanosensing |
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| Authors: | Jing Zhou Camilo Aponte-Santamaría Sebastian Sturm Jakob Tómas Bullerjahn Agnieszka Bronowska Frauke Gr?ter |
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| Institution: | 1. Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.; 2. Leipzig University, Institute for Theoretical Physics, Leipzig, Germany.; 3. Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.; University of Virginia, UNITED STATES, |
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| Abstract: | Mechanosensing at focal adhesions regulates vital cellular processes. Here, we present results from molecular dynamics (MD) and mechano-biochemical network simulations that suggest a direct role of Focal Adhesion Kinase (FAK) as a mechano-sensor. Tensile forces, propagating from the membrane through the PIP2 binding site of the FERM domain and from the cytoskeleton-anchored FAT domain, activate FAK by unlocking its central phosphorylation site (Tyr576/577) from the autoinhibitory FERM domain. Varying loading rates, pulling directions, and membrane PIP2 concentrations corroborate the specific opening of the FERM-kinase domain interface, due to its remarkably lower mechanical stability compared to the individual alpha-helical domains and the PIP2-FERM link. Analyzing downstream signaling networks provides further evidence for an intrinsic mechano-signaling role of FAK in broadcasting force signals through Ras to the nucleus. This distinguishes FAK from hitherto identified focal adhesion mechano-responsive molecules, allowing a new interpretation of cell stretching experiments. |
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