Cutting edge: Functional role for proline-rich tyrosine kinase 2 in NK cell-mediated natural cytotoxicity

Protein tyrosine kinase activation is one of the first biochemical events i n the signaling pathway leading to activation of NK cell cytolytic machiner y. Here we investigated whether proline-rich tyrosine kinase 2 (Pyk2), the nonreceptor protein tyrosine kinase belonging to the focal adhesion kinase family, could play a role in NR cell-mediated cytotoxicity. Our results dem onstrate that binding of NK cells to sensitive target cells or ligation of beta(2) integrins results in a rapid induction of Pyk2 phosphorylation and activation. By contrast, no detectable Pyk2 tyrosine phosphorylation is fou nd upon CD16 stimulation mediated by either mAb or interaction with Ab-coat ed P815 cells. A functional role for Pyk2 in natural but not Ab-mediated cy totoxicity was demonstrated by the use of recombinant vaccinia viruses enco ding the kinase dead mutant of Pyk2. Finally, we provide evidence that Pyk2 is involved in the beta(2) integrin-triggered extracellular signal-regulat ed kinase activation, supporting the hypothesis that Pyk2. plays a role in the natural cytotoxicity by controlling extracellular signal-regulated kina se activation.