Abstract
Physical forces play important roles in regulating cell proliferation, differentiation, and death by activating intracellular signal transduction pathways. How cells sense mechanical stimulation, however, is largely unknown. Most studies focus on cellular membrane proteins such as ion channels, integrins, and receptors for growth factors as mechanosensory units. Here we show that mechanical stretch-induced c-Src protein tyrosine kinase activation is mediated through the actin filament-associated protein (AFAP). Distributed along the actin filaments, AFAP can directly active c-Src through binding to its Src homology 3 and/or 2 domains. Mutations at these specific binding sites on AFAP blocked mechanical stretch-induced c-Src activation. Therefore, mechanical force can be transmitted along the cytoskeleton, and interaction between cytoskeletal associated proteins and enzymes related to signal transduction may convert physical forces into biochemical reactions. Cytoskeleton deformation-induced protein-protein interaction via specific binding sites may represent a novel intracellular mechanism for cells to sense mechanical stimulation.
Highlights
Sensing external and internal stimuli is a vital sign of living organisms
Cells attach to the extracellular matrix (ECM)1 via integrins that link to the cytoskeleton
Tschumperlin et al reported that compressive stress shrinks the lateral intercellular space surrounding epithelial cells and triggers cellular signaling via autocrine binding of epidermal growth factor (EGF) family ligands to the EGF receptor [19]
Summary
The cell membrane proteins polycystin-1 and polycystin-2 have been found to mediate mechanosensation in the primary cilium of kidney cells [15] In these structures, transduction channels connected to intracellular and extracellular anchors control the entry of ions, converting a mechanical stimulus into an electrical signal, an alteration of membrane potential [13]. Tschumperlin et al reported that compressive stress shrinks the lateral intercellular space surrounding epithelial cells and triggers cellular signaling via autocrine binding of epidermal growth factor (EGF) family ligands to the EGF receptor [19]. This observation again supports the importance of cellular membrane proteins in mechanosensory processes. Based on the molecular structure of c-Src and AFAP, we hypothesized that the cytoskeletal structure can transmit physical forces
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