The Fc epsilon RI complex forms a high-affinity
cell-surface receptor interaction for the Fc region of antigen-specific immunoglobulin E
(IgE) molecules. Fc epsilonRI
controls the activation of mast cells and basophils, and participates in IgE-mediated
antigen presentation. Fc epsilon RI is the central to the
induction and maintenance of an allergic response and may confer physiological protection
in parasitic infections. This receptor induces multiple signaling pathways that control
the secretion of allergic mediators and induction of cytokine gene transcription,
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 .
Human mast cells and basophils express Fc epsilon RI that
consists of three subunits -alpha,beta, gamma, and formes tetramer (AlphaBetaGamma2).
However, the Fc epsilon RI on the surface of human monocytes
consist of alpha and gamma subunits and form a trimeric (AlphaGamma2) complex. The
Alpha-chain binding with IgE and the others subunits are essential for downstream
After Fc epsilon RI aggregation by
antigen-induced-crosslinking the immunoglobulin E, beta-subunit-associated
LYN is activated and phosphorylates immunoreceptor
tyrosine-based activation motifs (ITAMs) in the beta and gamma subunits of Fc epsilon
RI. Phosphorylated ITAMs of the beta- and gamma- subunits
recruit additional molecules of LYN and
SYK. SYK binding to the
Fc epsilon RI complex is activated through conformational
changes after tyrosine phosphorylation by LYN.
Activated SYK then phosphorylates many substrates,
including linker for activation of T Lcells (LAT),
SH2-domain-containing leukocyte protein of 76 kDa (SLP76),
VAV, GRB2-associated binding protein 2
(GAB2), and Phospholipase C gamma
(PLC-gamma), which leads to the activation of several signaling pathways
Phosphorylation of GAB2 result its recruitment to
membrane and activation of Phosphatidylinositol 3-kinase
(PI3K), which catalyses the synthesis of
and thereby stimulates the AKT signaling pathway.
Phosphorylation of LAT results in recruitment of
guanine-nucleotide exchange factor SOS complexed to adaptor
protein GRB2. SOS activates
small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog
(H-RAS) leading to initiation of
H-RAS/ v-raf-1 murine leukemia
viral oncogene homolog 1 (c-RAF)/ Mitogen-activated protein
kinase kinases 1 and 2 (MEK1 and
MEK2)/ Mitogen-activated protein kinases 3 and 1
(ERK1 and ERK2) signaling
cascade that targets the Elk1 transcription factor. Moreover
ERK phosphorylation activates cytosolic Phospholipase A2
(PLA2) contributing to the secretion of leukotrienes and
prostaglandins, leading to inflammatory responses .
Additionally, phosphorylated stimulated the recruitment
of PLC-gamma to the plasma membrane, which becomes a target
of BTK (Bruton tyrosine kinase) and
SYK. BTK itself becomes
activated through phosphorylation by LYN and
SYK , .
LAT associates with both isoforms PLC-gamma
1 and 2, whereas
SYK associates with PLC-gamma 2
. Phosphorylated PLC-gamma generates
diacylglycerol (DAG) and Inositol-1,4,5-trisphosphate
(IP3) from Phosphatidylinositol-4,5-bisphosphate
DAG activates many isoforms of Protein kinase C (PKC),
including PKC-theta. PKC-theta
activates I-kappa-B kinase
(IKK) resulting in NF-kB
IP3 activates IR3 receptors
(IP3R) that results in the release of
Ca2+ from intracellular storage- endoplasmic
reticulum. In the endoplasmic-reticulum, calcium-bound
Calmodulin associates with and activates serine/threonine
NFAT family of transcription factors leading to their
translocation to the nucleus .
Moreover stimilation of the Fc epsilon RI complex
induces activation MAP-kinase cascades.
SYK activates the downstream c-Jun N-terminal kinase (JNK)
via phosphorylation SLP76 and
VAV. VAV is exchange factor for
small GTPase Rac1 and activates
cascade. Accordingly, SYK couples the Fc
epsilon RI complex to with the JNK cascade
The Fc epsilon RI complex also activates
p38 MAP kinase cascade, perhaps via phosphorylation
FER tyrosine kinase by LYN.
FER can activate p38 via
MKK3 and MKK6 .
Fc epsilon RI induction of
ERK, JNK and
p38 MAP kinase cascades result in the activation of
transcription factors regulating the AP-1 complex (c-jun,
ATF-2) and NF-AT,
NF-kB, which are crucial for immune response signaling.
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