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Jefferson Medical College, Kimmel Cancer Center, Philadelphia, PA 19107
Extracellular signal-regulated kinases (ERK, also known as
mitogen-activated protein kinases) are serine-threonine kinases
transducing signals elicited upon ligand binding to several tyrosine
kinase-associated receptors. We have reported that ERK2 phosphorylation
and activation follows engagement of the low affinity receptor for the
Fc portion of IgG (CD16) on NK cells, and is necessary for CD16-induced
TNF-
mRNA expression. Here, we analyzed the involvement of ERK in NK
cell-mediated cytotoxicity and IFN-
expression induced upon
stimulation with targets cells, coated or not with Abs. Our data
indicate that, as with immune complexes, ERK2 phosphorylation occurs in
human primary NK cells upon interaction with target cells sensitive to
granule exocytosis-mediated spontaneous cytotoxicity, and that this
regulates both target cell- and immune complex-induced cytotoxicity and
IFN- mRNA expression. A specific inhibitor of mitogen-activated
protein kinase kinase reduced both spontaneous and Ab-dependent
cytotoxicity in a dose-dependent manner involving, at least in part,
inhibition of granule exocytosis without affecting effector/target cell
interaction and rearrangement of the cytoskeleton proteins actin and
tubulin. Involvement of ERK in the regulation of
Ca2+-dependent cell-mediated cytotoxicity was confirmed,
using a genetic approach, in primary NK cells infected with a
recombinant vaccinia virus encoding an ERK inactive mutant. These data
indicate that the biochemical pathways elicited in NK cells upon
engagement of receptors responsible for either spontaneous or
Ab-dependent recognition of target cells, although distinct, utilize
ERK as one of their downstream molecules to regulate effector
functions.
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