Capn4 forces the issue

When cells migrate across a substrate, they dynamically form and disassemble focal adhesions and, through these, exert traction forces on the substrate and receive physical signals from the environment. The calpains – which are Ca²⁺-dependent cysteine proteases – are thought to regulate focal-adhesion dynamics, but do they have a role in traction-force regulation and mechanosensing? To address this question, Karen Beningo and colleagues (p. 3581) analyse the behaviour of fibroblasts that lack Capn4 (which encodes the small regulatory subunit that is common to the ubiquitous calpains 1 and 2) on flexible polyacrylamide substrates. The authors show that Capn4^–/– cells generate weaker and less-dynamic traction forces than control cells, and adhere less strongly to the substrate. Surprisingly, however, knocking down Capn1 or Capn2 (the catalytic subunits of calpain 1 and 2, respectively) does not cause defects in force generation or adhesion. The authors next show that Capn4^–/– cells and Capn1- and Capn2-knockdown cells are all deficient in mechanosensing; they fail to respond to pushing or pulling of the substrate, or to the engagement of dorsal integrins. The Capn4 gene product might, the authors propose, have as-yet-unknown functions that go beyond its role as a regulatory subunit.