Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells

The mitogen-activated protein kinase-extracellular signal-regulated kinase signaling element (MAPK-ERK) plays a critical role in natural killer (NK) cell lysis of tumor cells, but its upstream effecters were previously unknown. We show that inhibition of phosphoinositide-3 kinase (PI3K) in NK cells blocks p21-activated kinase 1 (PAK1), MAPK kinase (MEK) and ERK activation by target cell ligation, interferes with perforin and granzyme B movement toward target cells and suppresses NK cytotoxicity. Dominant-negative N17Rac1 and PAK I mimic the suppressive effects of PI3K inhibitors, whereas constitutively active V12Rac1 has the opposite effect. V12Rac1 restores the activity of downstream effecters and lytic function in LY294002- or wortmannin-treated, but not PD98059-treated, NK cells,These results document a specific PI3K-->Rac1-->PAK1->MEK-->ERK pathway in NK cells that effects lysis.