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.
Highlights
Focal adhesions (FAs) act as key cellular locations for mechanosensing by integrating mechanical and biochemical signals between the outside and inside of the cell, thereby regulating processes such as cell proliferation, motility, differentiation, and apoptosis [1,2,3]
We show that anchorage of Focal Adhesion Kinase (FAK) to the membrane via PIP-2 is critical for this mechanical activation
Phosphorylation of the activation loop of FAK is enhanced by relieving the autoinhibition through Y180/M183 mutation [14] or PIP2-binding [18]
Summary
Focal adhesions (FAs) act as key cellular locations for mechanosensing by integrating mechanical and biochemical signals between the outside and inside of the cell, thereby regulating processes such as cell proliferation, motility, differentiation, and apoptosis [1,2,3]. They contain numerous adapter or anchor proteins, which establish the mechanical link of the cytoskeleton with the extracellular matrix [4]. Focal Adhesion Kinase (FAK) centrally regulates FAs by establishing adhesive interactions at the cell periphery [8]. The N-terminal threelobed 4.1 ezrin radixin moesin (FERM) homology domain is connected to the kinase N-lobe doi:10.1371/journal.pcbi.1004593.g001
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