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Immune response Fc epsilon RI pathway


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Immune response Fc epsilon RI pathway

Fc-epsilon RI pathway

The Fc epsilon RI complex forms a high-affinity cell-surface receptorinteraction for the Fc region of antigen-specific immunoglobulin E ( IgE )molecules. Fc epsilonRI controls the activation of mast cells and basophils, andparticipates in IgE-mediated antigen presentation. Fc epsilon RI is the central tothe induction and maintenance of an allergic response and may confer physiologicalprotection in parasitic infections. This receptor induces multiple signaling pathwaysthat control the secretion of allergic mediators and induction of cytokine genetranscription, resulting in secretion of molecules such as Interleukins:IL-4, IL-5, IL-6,IL-10, IL-13, INF-Gamma (Interferon-Gamma), TNF-Alpha (tumour-necrosis factor-alpha),GCSF (granulocyte-macrophage colony-stimulating factor) to name few [1].

Human mast cells and basophils express Fc epsilon RI that consists of threesubunits -alpha,beta, gamma, and formes tetramer (AlphaBetaGamma2). However, the Fcepsilon RI on the surface of human monocytes consist of alpha and gamma subunits andform a trimeric (AlphaGamma2) complex. The Alpha-chain binding with IgE and the otherssubunits are essential for downstream signaling [2].

After Fc epsilon RI aggregation by antigen-induced-crosslinking the immunoglobulin E, beta-subunit-associated LYN is activated and phosphorylatesimmunoreceptor tyrosine-based activation motifs (ITAMs) in the beta and gamma subunitsof Fc epsilon RI. Phosphorylated ITAMs of the beta- and gamma- subunits recruitadditional molecules of LYN and SYK. SYK binding to the Fcepsilon RI complex is activated through conformational changes after tyrosinephosphorylation by LYN.

Activated SYK then phosphorylates many substrates, including linker foractivation of T Lcells ( LAT ), SH2-domain-containing leukocyte protein of 76 kDa(SLP76 ), VAV, GRB2-associated binding protein 2 (GAB2 ), andPhospholipase C gamma (PLC-gamma ), which leads to the activation of severalsignaling pathways [1], [3].

Phosphorylation of GAB2 result its recruitment to membrane and activation ofPhosphatidylinositol 3-kinase ( PI3K ), which catalyses the synthesis ofPhosphatidylinositol-3,4,5-trisphosphate ( PIP 3 ) and therebystimulates the AKT signaling pathway.

Phosphorylation of LAT results in recruitment of guanine-nucleotide exchangefactor SOS complexed to adaptor protein GRB2. SOS activates smallGTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS ) leading toinitiation of H-RAS/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-RAF )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1 andMEK2 )/ Mitogen-activated protein kinases 3 and 1 ( ERK1 and ERK2 )signaling cascade that targets the Elk1 transcription factor. Moreover ERKphosphorylation activates cytosolic Phospholipase A2 ( PLA2 ) contributing to thesecretion of leukotrienes and prostaglandins, leading to inflammatory responses [4].

Additionally, phosphorylated stimulated the recruitment of PLC-gamma to theplasma membrane, which becomes a target of BTK (Bruton tyrosine kinase) andSYK. BTK itself becomes activated through phosphorylation by LYNand SYK [5], [6]. LAT associates with bothisoforms PLC-gamma 1 and 2, whereas SYK associates withPLC-gamma 2 [7]. Phosphorylated PLC-gamma generatesdiacylglycerol ( DAG ) and Inositol-1,4,5-trisphosphate ( IP 3 )from Phosphatidylinositol-4,5-bisphosphate ( PI(4,5)P 2 ) [8].

DAG activates many isoforms of Protein kinase C (PKC), includingPKC-theta. PKC-theta activates I-kappa-B kinase ( IKK ) resultingin NF-kB activation [9].

IP 3 activates IR3 receptors ( IP3R ) that results in therelease of Ca 2+ from intracellular storage- endoplasmic reticulum. Inthe endoplasmic-reticulum, calcium-bound Calmodulin associates with and activatesserine/threonine phosphatase Calcineurin. Calcineurin dephosphorylatesNFAT family of transcription factors leading to their translocation to the nucleus[10].

Moreover stimilation of the Fc epsilon RI complex induces activation MAP-kinasecascades. SYK activates the downstream c-Jun N-terminal kinase (JNK) viaphosphorylation SLP76 and VAV. VAV is exchange factor for smallGTPase Rac1 and activates Rac1 - PAK2 - MEKK1 - MKK4/7- JNK cascade. Accordingly, SYK couples the Fc epsilon RI complex towith the JNK cascade [11].

The Fc epsilon RI complex also activates p38 MAP kinase cascade, perhapsvia phosphorylation FER tyrosine kinase by LYN. FER can activatep38 via MKK3 and MKK6 [12].

Fc epsilon RI i nduction of ERK, JNK and p38 MAP kinasecascades result in the activation of transcription factors regulating the AP-1 complex (c-jun, ATF-2 ) and NF-AT, NF-kB, which are crucial forimmune response signaling[13].