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

Nat Immunol. 2000 Nov;1(5):419-25. doi: 10.1038/80859.

Abstract

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 PI3K-->Rac1-->PAK1-->MEK-->ERK pathway in NK cells that effects lysis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line
  • Cytotoxicity, Immunologic*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • In Vitro Techniques
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / enzymology*
  • Killer Cells, Natural / immunology*
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • MAP2K2 protein, human
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • rac1 GTP-Binding Protein