p66^Shc mediates anoikis through RhoA

Detachment of parenchymal cells from a solid matrix switches contextual cues from survival to death during anoikis. Marked shape changes accompany detachment and are thought to trigger cell death, although a working model to explain the coordination of attachment sensation, shape change, and cell fate is elusive. The constitutive form of the adapter Shc, p52^Shc, confers survival properties, whereas the longer p66^Shc signals death through association with cytochrome c. We find that cells that lack p66^Shc display poorly formed focal adhesions and escape anoikis. However, reexpression of p66^Shc restores anoikis through a mechanism requiring focal adhesion targeting and RhoA activation but not an intact cytochrome c–binding motif. This pathway stimulates the formation of focal adhesions and stress fibers in attached cells and tension-dependent cell death upon detachment. p66^Shc may thus report attachment status to the cell by imposing a tension test across candidate anchorage points, with load failure indicating detachment.