Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity
in natural killer cells
Kun Jiang1, Bin Zhong1, Danielle L. Gilvary1, Brian C. Corliss1, Elizabeth Hong-Geller2, Sheng Wei1
& Julie Y. Djeu1
1
Immunology Program, H. Lee Moffitt Cancer Center, Department
of Interdisciplinary Oncology, University of South Florida College of Medicine,
Tampa, FL 33612, USA.
2
Los Alamos National Laboratories, Los Alamos,
NM 87545, USA.
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 effectors 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 PAK1 mimic the suppressive effects of PI3K inhibitors, whereas constitutively
active V12Rac1 has the opposite effect. V12Rac1 restores the activity of downstream
effectors and lytic function in LY294002- or wortmannin-treated, but not PD98059-treated,
NK cells. These results document a specific PI3KRac1PAK1MEKERK
pathway in NK cells that effects lysis.
Rac1
