p66Shc checks the cell's anchor points (yellow) to ensure a good grip.

Like soloing rock climbers, adherent cells need a good handhold to survive. Ma et al. now identify an adaptor protein that monitors the cell's grip and signals death if the grip fails.

Death following detachment, known as anoikis, is a form of programmed cell death that ensures the disposal of displaced adherent cells. Lack of anoikis is thought to give cells metastatic potential.

A number of survival factors have been identified that are activated by integrin attachment to the extracellular matrix. Binding to soluble matrix fragments, rather than to a fixed matrix, does not prevent anoikis. This difference suggests that mechanical tension is also being measured.

Inside the cell, integrins associate with signaling adaptor proteins of the Shc family. One family member, p66Shc, has been suggested to promote apoptosis. The team now shows that an epithelial cell line that resists anoikis does not express p66Shc. Giving these cells back some p66Shc reestablished detachment-induced death. Normal epithelial and endothelial cells express p66Shc. Thus, p66Shc must only trigger death upon cell detachment.

p66Shc did not induce anoikis by the same mechanism as it induces apoptosis. For apoptosis, p66Shc enters mitochondria. But for anoikis, p66Shc associated with integrins and activated the actin cytokeleton regulator RhoA.

RhoA increases tension between cell attachment points by inducing stress fiber formation. Inhibiting contraction of these fibers, the team showed, curbed anoikis. The authors therefore suggest that the cell continuously checks its tension by contracting its stress fibers—like checking from the inside of a tent whether the pegs are secure. If the cell contracts easily, then p66Shc signals that external anchors are missing and that, for this cell, the camping trip is over.


Ma, Z., et al.
J. Cell Biol.