title: Mechanism of Focal Adhesion Kinase Mechanosensing.
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.
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
authors.forename: Camilo
authors.initials: C
authors.lastname: Aponte-Santamaría
authors.affiliation: Leipzig University, Institute for Theoretical Physics, Leipzig, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Sturm
authors.affiliation: Leipzig University, Institute for Theoretical Physics, Leipzig, Germany.
authors.forename: Jakob Tómas
authors.initials: JT
authors.lastname: Bullerjahn
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bronowska
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.|Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
mesh_terms: D019295:Computational Biology; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D003599:Cytoskeleton / Q000737:chemistry / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D022001:Focal Adhesions / Q000737:chemistry / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D056004:Molecular Dynamics Simulation
chemical_list: D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases