Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity

Authors:
Chen X, Trivedi PP, Ge B, Krzewski K, Strominger JL
In:
Source: Proc Natl Acad Sci USA
Publication Date: (2007)
Issue: 104(15): 6329-34
Research Area:
Immunotherapy / Hematology
Cells used in publication:
K-562
Species: human
Tissue Origin: blood
721.221
Species: human
Tissue Origin: blood
NK-92
Species: human
Tissue Origin: blood
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
Natural killer (NK) cells are components of the innate immune system that recognize and kill tumor or virus-infected target cells through specific NK activating receptor/ligand interactions. Lymphocyte function-associated antigen (LFA)-1 and its ligand ICAM-1 are also required to initiate conjugation and actin cytoskeletal remodeling. The NK activating receptors, many of which are expressed on a single NK cell, signal the polarization of the microtubule organizing center (MTOC) together with cytolytic granules to the synapse with target cells. After ligation of any one of these receptors, Src family kinases initiate activation of two signal pathways, the phosphoinositide-3 kinase --> ERK2 and the phospholipase Cgamma --> JNK1 pathways. Both are required for polarization of the MTOC and cytolytic granules, a prerequisite for killing the targets. Crosslinking of CD28, NKG2D, NKp30, NKp46, NKG2C/CD94, or 2B4 leads to the phosphorylation of both ERK2 and JNK1, although they use different proximal signaling modules. Thus, many, if not all, activating receptors stimulate these two distal pathways, independent of the proximal signaling module used. By contrast, CD2, DNAM-1, and beta(1)-integrin crosslinking do not activate either pathway; they may be costimulatory molecules or have another function in the synapse.