Stretchable force sensors

Cells in the body somehow sense that they are continually being pushed and pulled. Yasuhiro Sawada, Michael Sheetz (Columbia University, New York, NY), and colleagues now reveal that cellular tension causes a normally coiled cytoskeletal protein to stretch out and, in so doing, communicate the force downstream. The resulting signals help to direct cells toward areas of lower tension during wound healing and development.

Sheetz's group previously showed that stretching the cell's entire cytoskeleton triggered phosphorylation of a cytoskeletal protein called p130Cas, which is found at cell–matrix contact sites. The inference was that p130Cas itself was stretched and that this stretching was required for its phosphorylation, but formal proof was lacking.

So the group set up a test system with a modified p130Cas. Biotinylation of both ends of p130Cas allowed it to be attached to and stretched by an avidin-coated latex sheet. Stretching was confirmed based on a loss of YFP fluorescence, as the YFP was split between the two ends of p130Cas.

Stretching the latex caused p130Cas to extend and become phosphorylated, presumably because its phosphorylation sites were now exposed. More vigorous stretching of the membrane led to more (and distinct) residues being phosphorylated. These phosphorylated residues allow docking of proteins that turn on the Rap1/MAPK pathway, and having more of them may increase how far the cell spreads in a given direction.

In vivo, the team used antibodies that recognized either the phosphorylated or stretched forms of p130Cas. As they saw in vitro, p130Cas stretching and phosphorylation were correlated. Both antibodies localized specifically to the cell periphery, the region that absorbs most of the pulling in living, moving cells.

The change in p130Cas conformation effectively converts a mechanical stimulus into a biochemical signal. Sawada says this could be a general mechanism for cell signaling and that other cytoskeletal proteins might transduce signals in a similar way. The results suggest that the cytoskeleton is not just a cellular scaffold but also a force sensing radar for the cell.

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