NFAT in immune response
The Nuclear factors of activated T cells
(NFAT) transcription factors family plays a
pivotal role in initiation and coordination of the immune response in a different types
of immune system cells, including T- and B cells, mast cells, basophiles and natural
killer cells .
The induction of an immune response requires that T cells receive 2 sets of signals
from antigen-presenting cells. The first signal is delivered through the T-cell receptor
complex, while the second is provided by the B-cell activation antigens CD80 molecule
(CD80) and CD86 molecule
(CD86), by interaction with the T-cell surface molecules,
CD28 molecule (CD28) , , .
The T-cell receptor complex (TCR/CD3 complex) is comprised of a ligand-binding T-cell
receptor alpha/beta heterodimer complexes (TCR alpha/beta)
and signaling subunits CD3 molecules (CD3). The physiologic
ligand for the TCR alpha/beta is foreign peptide bound to
the Major histocompatibility complex, class II (MHC class
II) expressed on antigen-presenting cells . Upon
activation of the TCR, the Lymphocyte-specific protein tyrosine kinase
(Lck) becomes activated. The activated
Lck phosphorylates the CD247 molecule (CD3
zeta), which promotes the recruitment and subsequent activation of another
Zeta-chain (TCR) associated protein kinase 70kDa (ZAP-70)
One of the known substrates of ZAP-70 is the adapter
molecule Linker for activation of T cells (LAT). The
phosphorylation of tyrosine residues on LAT results in
recruitment and activation Phospholipase C, gamma 1 (PLC-gamma
1). The other target for ZAP-70 is the
adaptor protein Lymphocyte cytosolic protein 2 (SLP76),
which recruits Vav 1 guanine nucleotide exchange factor
(VAV-1). VAV-1 activates
Ras-related C3 botulinum toxin substrate 1 (Rac1)
that participates in actin cytoskeletal remodeling .
CD28, in response to ligation by antigens
CD80 and CD86, recruits T
cell-specific tyrosine kinase IL2-inducible T-cell kinase
(ITK), which phosphorylates and activates
The B-Cell antigen Receptor (BCR) plays a critical role in the activation of B
lymphocytes and regulation of immune response. The BCR is composed of membrane
immunoglobulin (IgM) molecules and associated with CD79a
molecule, immunoglobulin-associated alpha - CD79b molecule, immunoglobulin-associated
beta heterodimers (CD79 complex) . The
IgM subunits bind antigen and cause receptor aggregation,
while the CD79 complex transduces signals to the cell
interior. Receptor engagement leads to the activation of intracellular protein tyrosine
kinases Syk and Lyn, which
phosphorylate and activate phospholipases PLC-gamma-1 and
-2, and Bruton tyrosine kinase
(BTK), respectively. BTK also
activates both PLC-gamma isoforms , .
The high-affinity IgE receptor (Fc epsilon RI), which is
expressed on the surface of mast cells and basophils, has a central role in immediate
allergic responses . The aggregation of the high affinity IgE receptor
(Fc epsilon RI) to the antigen results in activation of the
protein tyrosine kinases Spleen tyrosine kinase (Syk) and
v-yes-1 Yamaguchi sarcoma viral related oncogene homolog
(Lyn), leading to PLC-gamma 1
and 2 activation .
Activated PCL-gamma in the all types of these cells is
responsible for the production of the second messengers diacylglycerol
(DAG)and inositol 1,4,5-triphosphate
(IP3) by cleaving phospha-tidylinositol 4,5 bisphosphate
(PtdIns(4,5)P2) at the plasma membrane.
IP3 binds Inositol 1,4,5-triphosphate receptor
(IP3 Receptor), which is localized primarily on the
endoplasmic reticulum and stimulates the release of calcium from intracellular stores.
Calcium-bound Calmodulin 2 (Calmodulin) associates with and
activates Protein phosphatase 3, catalytic subunit
(Calcineurin A (catalytic)).
Calcineurin A (catalytic) dephosphorylates
NF-AT1(NFATC2) leading to theirs translocation to the
DAG activates various isoforms of protein kinase C,
including Protein kinase C, theta (PKC-theta). It was shown,
PKC-theta activates kinase IKK-cat
complex by phosphorylation Inhibitor of kappa light polypeptide gene
enhancer in B-cells, kinase beta (IKK-beta). Active
IKK-cat phosphorylates of serine residues on the Nuclear
factor of kappa light polypeptide gene enhancer in B-cells inhibitor
(I-kB) proteins marks them for destruction via the
ubiquitination pathway, thereby allowing activation of the Nuclear factor of kappa light
polypeptide gene enhancer in B-cells (NF-kB) .
In addition, CD28 recruits Phosphoinositide-3-kinase,
(PI3K reg class IA) that stimulates
Phosphoinositide-3-kinase, catalytic (PI3K cat class IA).
PI3K cat class IA converts phosphatidylinositol
4,5-biphosphate (PtdIns(4,5)P2) to phosphatidylinositol
PtdIns(3,4,5)P3 in turn, associates with the inner bilayer
of the plasma membrane promoting the recruitment of proteins with pleckstrin homology
(PH) domains, such as the V-akt murine thymoma viral oncogene homolog 1
(AKT(PKB)). Activation of AKT(PKB)
participates in stimulation NF-kB via
Conserved helix-loop-helix ubiquitous kinase (IKK-alpha)
activation . Moreover, stimulated AKT(PKB)
blocks the action of Glycogen synthase kinase-alpha/beta
(GSK3alpha/beta), which phosphorylates Nuclear factor of
activated T-cells, cytoplasmic, calcineurin-dependent 4
(NF-AT3(NFATC4)), preventing its nuclear translocation
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