Cells lacking vinculin survive after detachment because they phosphorylate ERK.

Teasing apart the contributions of so many motility proteins has proven difficult. So Subauste et al. report in this issue that they turned to an all-or-none readout—apoptotic cell death—to answer some of the same questions (page 371). They find that the attachment and motility protein vinculin pokes its nose between paxillin and FAK, thus disrupting signal transduction that activates the survival signals sent by extracellular signal–related kinase (ERK).

After serum withdrawal, detachment from a substrate, or pro-apoptotic drug treatment, cells lacking vinculin were compared with wild-type cells. The cells lacking vinculin showed greater paxillin–FAK interaction, an increase in ERK phosphorylation, and reduced apoptosis.

The reduction in apoptosis (and increase in migration rates) could be reversed by ERK pathway inhibitors. This is reminiscent of the behavior of many cancer cell lines, which lack vinculin and are extremely metastatic and motile unless vinculin expression is restored.

Wild-type cells may survive when attached because of low level ERK signaling. That signaling must be repressed after detachment, in part via the interfering actions of vinculin. Cells lacking vinculin send an excess of the survival signal and thus fail to make the correct change in both their attachment structures and signaling pathways in response to the new nonadherent situation. ▪