Phosphorylation of Trask by Src kinases inhibits integrin clustering and functions in exclusion with focal adhesion signaling.

Trask is a recently described transmembrane substrate of Src kinases whose expression and phosphorylation has been correlated with the biology of some cancers. Little is known about the molecular functions of Trask, although its phosphorylation has been associated with cell adhesion. We have studied the effects of Trask phosphorylation on cell adhesion, integrin activation, clustering, and focal adhesion signaling. The small hairpin RNA (shRNA) knockdown of Trask results in increased cell adhesiveness and a failure to properly inactivate focal adhesion signaling, even in the unanchored state. On the contrary, the experimentally induced phosphorylation of Trask results in the inhibition of cell adhesion and inhibition of focal adhesion signaling. This is mediated through the inhibition of integrin clustering without affecting integrin affinity state or ligand binding activity. Furthermore, Trask signaling and focal adhesion signaling inactivate each other and signal in exclusion with each other, constituting a switch that underlies cell anchorage state. These data provide considerable insight into how Trask functions to regulate cell adhesion and reveal a novel pathway through which Src kinases can oppose integrin-mediated cell adhesion.