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adhesion marker, LFA-1, on the NK cell, can bind to ICAM-1 on the target
cell and initiate signal transduction. Other NK cell receptors enhance NK
cell adherence, such as CD2, CD16, and 2B4. Following adhesion to the
target cell, activating receptors can now bind to their ligands. The ITAM-
bearing activating receptors on NK cells use transmembrane adaptors
that posses intracellular signaling domains to begin the activation cas-
cade. CD16, NKp30, and NKp46 can dimerize with FcεRIγ or CD3ζ or both,
whereas NKp44 uses DAP-12. The activating KIR, activating Ly49, NKG2C,
and NKG2E all couple with DAP-12. Upon ligation, protein tyrosine kinases
of the Src family phosphorylate ITAM-bearing subunits. This leads to
recruitment of ZAP-70 and/or Syk, initiating further downstream signal-
ing cascades, ultimately leading to polarization of perforin and granzyme-
containing granules and release of these cytotoxic granules to lyse the
target cell. The ITAM-dependent NKG2D receptor couples with DAP-10 in
humans, whereas in mice it can couple to both DAP-12 and DAP-10. Upon
ligation DAP-10 signaling recruits either p85 or Grb2, leading to the phos-
phorylation of PI3K, when p85 binds, or SLP-76, Vav1, and PLC-y2, if Grb2
binds, ultimately leading to increased Ca
2+
influx and release of cytotoxic
granules
[23]
. Members of the SLAM family of receptors, which includes
2B4, contain a signaling motif called an immunoreceptor tyrosine-based
switch motif (ITSM). Upon ligation the ITSM is recognized by three cyto-
plasmic SH2-domain-containing adaptor molecules: SAP, EAT, and ERT.
Mutation of SAP that results in loss of its function results in X-linked lym-
phoproliferative disease. 2B4 signaling recruitment of SAP is thought to
activate NK cells, whereas recruitment of EAT or ERT is thought to inhibit
NK cell activation
[23]
.
333
As NK cells express a wide range of activating receptors that interact with
various adaptor molecules and signal through different pathways to medi-
ate their effects, defects in one signaling pathway do not ultimately lead to
dysfunction. Mice lacking the tyrosine kinases ZAP-70 and Syk, and there-
fore having non-functional ITAMs, can still lyse tumor targets by presumably
upregulating ITAM-independent signaling pathways. It is also apparent
that separate pathways are involved in cytotoxicity and cytokine signal-
ing, and disassociation between the abilities to degranulate and to produce
cytokines may be related to differing signaling pathways. Colucci and col-
leagues
[25]
studied the role of Vav1 in NK cell signaling and found that
Vav1
−/−
mice develop NK cells normally, but these NK cells are capable only
of target cell-induced IFN-γ production and are unable to lyse target cells.
Vav1 was shown to control ERK activation and exocytosis of cytotoxic gran-
ules, whereas it was clearly not involved in signaling for cytokine produc-
tion. Another study investigated divergent signaling pathways by focusing
on the role of CD45 in triggering cytotoxicity and cytokine production
[26]
.
CD45
−/−
mice were able to lyse targets but were unable to produce IFN-γ. It
was demonstrated that CD45 was required for the full activation of Syk and
Vav1 and phosphorylation of JNK and p38 after ITAM activation. However,
CD45 has no effect on ITAM-mediated P13K activity required for signaling
of cytotoxicity. As most activating receptors can signal for both cytotoxicity
and cytokine production, it is unclear if activating receptors trigger both
pathways simultaneously, or if cytotoxicity and cytokine production are
triggered at different signal thresholds.
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