NF-AT1(NFATC2), CD86, Ca('2+) cytosol, IKK-alpha, <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), IKK (cat), CD3 zeta, VAV-1, PtdIns(3,4,5)P3, 18.104.22.168, BLNK, ZAP70, 22.214.171.124, DAG, CD3, Rac1, TCR alpha/beta, Fc epsilon RI, I-kB, IP3, GSK3 alpha/beta, IKK-gamma, Calcineurin A (catalytic), NF-AT3(NFATC4), NF-kB, Ca('2+) endoplasmic reticulum lumen, CD28, Lyn, AKT(PKB), TRIM, IP3 receptor, ITK, Slp76, PI3K reg class IA, PKC-theta, IKK-beta, NF-AT, PLC-gamma 2, Btk, Syk, LAT, CD79 complex, Lck, Calmodulin, IgM, PI3K cat class IA, MHC class II, PtdIns(4,5)P2, IgE, PLC-gamma 1, CD80
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 PCL-gamma-1 .
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 nucleus .
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, regulatory subunit ( 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 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ). 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 .