Mechanism of Focal Adhesion Kinase Mechanosensing

PLoS Comput Biol. 2015 Nov 6;11(11):e1004593. doi: 10.1371/journal.pcbi.1004593. eCollection 2015 Nov.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / metabolism
  • Cytoskeleton / chemistry
  • Cytoskeleton / metabolism
  • Focal Adhesion Protein-Tyrosine Kinases / chemistry
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Focal Adhesions / chemistry
  • Focal Adhesions / metabolism*
  • Mechanotransduction, Cellular / physiology*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Models, Biological*
  • Molecular Dynamics Simulation

Substances

  • Cytoskeletal Proteins
  • Membrane Proteins
  • Focal Adhesion Protein-Tyrosine Kinases

Grants and funding

Funding from the Klaus Tschira Foundation (to JZ and FG), the BMBF SYSTEC programme (to JZ and FG), the Deutsche Forschungsgemeinschaft (DFG) research group FOR 1543 (to CAS and FG), and the BIOMS programme at Heidelberg University (to AB) is gratefully acknowledged. JTB and SS acknowledge financial support from the European Union and the Free State of Saxony, and the DFG through FOR 877 and the Leipzig School of Natural Sciences -Building with Molecules and Nano-objects (BuildMoNa). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.