Figure 7. Proposed model to explain both rigidity and tether length sensing.

(a) The force transducer (FT) molecule (green spring) is coupled such that an ECM-integrin-FT-actin chain exists. On a stiff ECM (red spring) the transmembrane integrin remains at a fixed location whilst the rearward actin flow pulls on the FT. The FT experiences a force greater than the trigger force (F > Ft) which leads to stretching and signalling by exposure of cryptic binding sites. (b) On a soft ECM (blue spring) the integrin is unhindered and able to freely diffuse along the membrane as the actin rearward flow applies a force on the FT. The FT experiences a force lower than the trigger force (F < Ft) and therefore signalling does not occur. (c) A steadily increasing force profile for an elastic solid is assumed. Differential signalling can be understood by noting the time taken (dt) for the FT to reach the trigger force is less for a stiff substrate than one with intermediate stiffness. Given the periodic nature of the actin rearward flow, for a stiff substrate a greater time will be spent above the trigger force leading to greater signalling. For a soft substrate the FT may never reach the trigger force. (d) The integrin is tethered to a stiff substrate (or ECM) by a short flexible tether (black line). This provides tension against integrin movement, analogous to a stiff substrate and leading to FT signalling. (e) For a long flexible linker (wavy black line) the integrin is free to diffuse and signalling does not occur, analogous to a soft substrate. (f) For a flexible tether a different force profile occurs with a latent period followed by a sharp increase in force. Regardless of force profile, if the FT feels a force greater than the trigger force it will signal. A short linker is thus analogous to a stiff substrate and a long linker is analogous to a soft substrate.