JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D-mediated NK cell cytotoxicity

Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3017-22. doi: 10.1073/pnas.0712310105. Epub 2008 Feb 19.


Interaction of the activating receptor NKG2D with its ligands is a major stimulatory pathway for cytotoxicity of natural killer (NK) cells. Here, the signaling pathway involved after NKG2D ligation is examined. Either incubation of the NKG2D-bearing human NKL tumor cell line with K562 target cells or cross-linking with NKG2D mAb induced strong activation of the mitogen-activated protein (MAP) kinases. Selective inhibition of JNK MAP kinase with four different means of inhibition greatly reduced NKG2D-mediated cytotoxicity toward target cells and furthermore, blocked the movement of the microtubule organizing center (MTOC), granzyme B (a component of cytotoxic granules), and paxillin (a scaffold protein) to the immune synapse. NKG2D-induced activation of JNK kinase was also blocked by inhibitors of Src protein tyrosine kinases and phospholipase PLCgamma, upstream of JNK. Similarly, a second MAP kinase pathway through ERK was previously shown to be required for NK cell cytotoxicity. Thus, activation of two MAP kinase pathways is required for cytotoxic granule and MTOC polarization and for cytotoxicity of human NK cells when NKG2D is ligated.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • Cell Polarity / immunology*
  • Cytotoxicity Tests, Immunologic
  • Enzyme Activation / immunology
  • Flow Cytometry
  • Granzymes / metabolism
  • Humans
  • Immunoblotting
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Microscopy, Confocal
  • Microtubule-Organizing Center / metabolism
  • NK Cell Lectin-Like Receptor Subfamily K
  • Paxillin / metabolism
  • RNA, Small Interfering / genetics
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Signal Transduction / immunology*


  • Antibodies, Monoclonal
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K
  • Paxillin
  • RNA, Small Interfering
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • JNK Mitogen-Activated Protein Kinases
  • Granzymes