%0 Journal Article
%T Mechanism of Focal Adhesion Kinase Mechanosensing
%A Agnieszka Bronowska
%A Camilo Aponte-Santamar¨ªa
%A Frauke Gr£¿ter
%A Jakob T¨®mas Bullerjahn
%A Jing Zhou
%A Sebastian Sturm
%J -
%D 2015
%R 10.1371/journal.pcbi.1004593
%X 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
%K Biochemical simulations
%K Focal adhesions
%K Fats
%K Lipids
%K Cell membranes
%K Phosphorylation
%K Protein kinase signaling cascade
%K Ras signaling
%U https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004593