Integrins rely on clustering and conformational changes to strengthen their attachment to substrates. On page 1073, Alon et al. report that at least one immune cell integrin must also be anchored to the cytoskeleton to resist the shear forces that affect cells in the bloodstream.

Leukocytes use integrins and L-selectins to latch onto the endothelium in response to chemokine signaling. The recent observation that L-selectins must be attached to the cytoskeleton before such binding raised the question whether there is a similar requirement in the leukocyte.

Leukocytes expressing a mutant VLA-4 integrin that cannot attach to paxillin were less able to resist shear forces than cells expressing wild-type VLA-4. The clustering, avidity, and affinity of the mutant VLA-4 were not reduced relative to wild-type integrin. However, because paxillin is responsible for attachment to the cytoskeleton via talin, Alon et al. concluded that cytoskeletal binding is a key factor for mechanical strength of the bond.

The researchers do not know if cytoskeletal attachment is a common feature of immune cell integrins, but they plan to find out. In the meantime, they hypothesize that VLA-4 attachment to the cytoskeleton serves to dissipate the force generated when the cell first grabs onto the endothelium and then comes to a halt while under shear force. If that energy is not dissipated, either the bond between the integrin and endothelium is likely to break or the integrin may be ripped from the microvilli.