CD16 signaling in NK cells
Natural killer (NK) cells mediate antibody-depend cellular cytotoxicity through the Fc
fragment of IgG, low affinity IIIa and receptor (CD16a) (Fc gamma RIII
alpha (CD16)) , . The preferred ligands
for Fc gamma RIII alpha (CD16) on NK cells are
Immunoglobulins gamma 1 and 3 (IgG1 and
IgG3) , . Fc
gamma RIII alpha (CD16) covalently associates with the Membrane-bound
signaling adaptor CD247 molecule (CD3 zeta), which
transduces signal to cytoplasm , . Upon ligand binding and
receptor activation, CD3 zeta is phosphorilated by
Lymphocyte-specific protein tyrosine kinase (Lck) , followed by recruitment of SYK family kinases - Spleen tyrosine kinase
(Syk)  and Zeta-chain associated protein
kinase 70kDa (ZAP70) , .
Ligation of Fc gamma RIII alpha (CD16) stimulates
expression of many cytokines via Ca('2+) -depend mechanism
. Both ZAP70 and Syk
phosphorylate Linker for activation of T cells
(LAT) , .
LAT activates Phospholipases C gamma 1 and 2
(PLC-gamma 1 and 2), which
control intracellular concentration of Ca('2+) , . Ca('2+) activates Calmodulin 2
(Calmodulin)/ Protein phosphatase 3
(Calcineurin) signal. Activated Calcineurin
dephosphorylates Nuclear factor of activated T-cells cytoplasmic
calcineurin-dependent 2 (NF-AT1(NFATC2)).
NF-AT1(NFATC2), in turn, migrates to the nucleus and
activates transcription of cytokines Tumor necrosis factor
(TNF-alpha), Colony stimulating factor 2
(GM-CSF), Interleukin 2 (IL-2),
Interleukin 3 (IL-3), Interleukin 4
(IL-4) , Fas ligand
(FasL)  and, possibly, Interferon gamma
These cytokines play various roles in immune response. FasL
participates in lysis of target cells , , , , , .
The second mechanism leading to cytokines transcription in NK cells is by activation
of v-Ha-ras Harvey rat sarcoma viral oncogene homolog
(H-RAS) via SHC transforming protein 1
(Shc)/ Growth factor receptor-bound protein 2
(Grb2)/ Son of sevenless homologes
(SOS) cascade , .
H-RAS activates v-raf-1 murine leukemia viral oncogene
homolog 1 (c-Raf-1)/
Mitogen-activated protein kinase kinases 1 and 2
(MEK1(MAP2K1) and MEK2(MAP2K2))/ Mitogen-activated protein kinases 3 and 1 (ERK1 and
ERK2) cascade , , . ERK1 and ERK2
phosphorylate Jun oncogene (c-Jun) and V-fos
FBJ murine osteosarcoma viral oncogene homolog (c-Fos),
which form homo- and hetero-dimmers complex AP-1 and
participate in activation of transcription TNF-alpha , IL-2  and
On the other hand, Fc gamma RIII alpha (CD16) ligation
induces pathways leading to exocytosis of secretory lysosomes .
PLC-gamma 2 probably participates in the first pathway
leading to cytoskeleton rearrangement . It catalyzes diacylglycerol
(DAG) synthesis leading to activation of Protein kinase C
theta (PKC-theta) , .
PKC-theta phosphorylates Wiskott-Aldrich syndrome protein
interacting protein (WaspIP) which leads to separation of
WaspIP from Wiskott-Aldrich syndrome
(WASP), activation of WASP and,
eventually, rearrangement of Actin cytoskeletal through
Apr2/3 complex. Actin
cytoskeletal rearrangement may be also required for cytolysis of target
The second pathway leading to exocytosis starts from Syk
and ZAP70, which phosphorylates Vav 1 guanine nucleotide
exchange factor (VAV-1) directly , . Then VAV-1 participates in activation of
Ras-related C3 botulinum toxin substrate 1 (Rac1) , . This pathway proceeds from Rac1
to formation of granules , . In addition,
VAV-1 may activate Cell division cycle 42
(CDC42), which participates in activation of
WASP , .
Another pathway which leads to secretion of granules includes
Syk/ Cas-Br-M ecotropic retroviral transforming sequence
(c-Cbl)/ Phosphoinositide 3-kinase
(PI3K) cascade, which activates Pleckstrin homology, Sec7
and coiled-coil domains 1 (Cytohesin1). Grb2
probably helps to activate c-Cbl . Cytohesin1 activates
ADP-ribosylation factor 6 Arf6 , . From Arf6, signal proceeds to
Phosphatidylinositol-4-phosphate 5-kinase type I alpha
(PIP5K1A) and Phospholipase D1 phosphatidylcholine-specific
(PLD1) directly and/or via
PIP5K1A. The products of reactions of both
PIP5KA1 and PLD1 participate in
the vesicle secretion .
ERK2 also participates in degranulation via activation of
Phospholipase A2 group IIA (PLA2) by phosphorylation , .
Inhibitory receptor Killer cell lectin-like receptor subfamily C, member 1
(NKG2A) and Killer cell lectin-like receptor subfamily D,
member 1 (CD94) deactivate stimulation from Fc
gamma RIII alpha (CD16) after ligation Classical MHC class I molecules
major histocompatibility complex, class I E (HLA-E) to
NKG2A. It attracts Protein tyrosine phosphatase non-receptor
type 6 (SHP-1), which dephosphorylates CD3
zeta, Syk and
Fc gamma RIII alpha (CD16) autoregulates activation of
downstream signals trough CD3 zeta / Shc
/ Inositol polyphosphate-5-phosphatase 145kDa
(SHIP) pathway. The hypothetical mechanism consists of
SHIP participation in inhibition of
Ca('2+) -depend pathway and signal from
PI3K via decreased amount IP3
 and PtdIns(3,4,5)P3 .
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