CASPASES CLEAVE FOCAL ADHESION KINASE DURING APOPTOSIS TO GENERATE A FRNK-LIKE POLYPEPTIDE

Focal adhesion kinase (Fak) is a non-receptor protein-tyrosine kinase that stimulates cell spreading and motility by promoting the formation of contact sites between the cell and the extracellular matrix (focal adhesions). It suppresses apoptosis by transducing survival signals t hat emanate from focal adhesions via the clustering of transmembrane i ntegrins by components of the extracellular matrix. We demonstrate tha t Fak is cleaved by caspases at two distinct sites during apoptosis. T he sites were mapped to DQTD(772), which was preferentially cleaved by caspase-3, and VSWD704, which was preferentially cleaved by caspase-6 and cytotoxic T lymphocyte-derived granzyme B. The cleavage of Fak. d uring apoptosis separates the tyrosine kinase domain from the focal ad hesion targeting (FAT) domain. The carboxyl-terminal fragments that ar e generated suppress phosphorylation of endogenous Fak. and thus resem ble a natural variant of Fak, FRNK, that inhibits Fak activity by prev enting the localization of Fak to focal adhesions. The cleavage of Fak by caspases may thus play an important role in the execution of the s uicide program by disabling the anti-apoptotic function of Fak, Intere stingly, rodent Fak lacks an optimal caspase-3 consensus cleavage site although it is cleaved in murine cells undergoing apoptosis at an ups tream site. This appears to be the first example of a caspase substrat e where the cleavage sites are not conserved between species.