Chiu et al. reveal the first step in the pathway that allows endothelial cells to determine when they are under mechanical stress.
Cells throughout the body are constantly being bent, tugged, pushed, and twisted. With each beat of the heart, for instance, cells that line blood vessels stretch and are exposed to shear stress. Such deformations prod a plasma membrane protein called PECAM-1, which latches endothelial cells together. In turn, PECAM-1 forwards the signal to other proteins in the cell. Scientists knew that the activation of PECAM-1 involves its phosphorylation. The mystery was what affixed the phosphate to the protein.
Researchers suspect that PECAM-1 is part of a multi-protein sensor that clings to the cytoskeleton. To search for PECAM-1's activator, Chiu et al. soaked endothelial cells in detergent to remove most of the membrane and the cytoplasmic proteins, leaving just the insoluble components, including the cytoskeleton. Stretching these bare-bones cells fired up PECAM-1, meaning that the activating enzyme remained. By adding different compounds that inhibit phosphate-attaching kinases, Chiu et al. narrowed down the list of enzymes to three candidates: Fyn, Src, and Yes. Blocking each with RNAi indicated that only Fyn sticks phosphates onto PECAM-1. Fyn might belong to the same sensing complex as PECAM-1, the researchers conclude. They now want to determine how mechanical stress jolts Fyn into action. One possibility is that it nudges Fyn closer to PECAM-1.