Efficient and coordinated synthesis of the second messengers, including
Inositol-1,4,5-trisphosphate (IP3), Diacylglycerol
Phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), is
necessary for normal cell functioning. Production of secondary messengers is regulated by
a variety of membrane receptors and downstream signaling cascades.
IP3 signaling is initiated by its binding to cognate
receptors, such as B-cell antigen receptor (BCR) in B-cells,
TCR/CD3 complex in T-cells,
PDGFR in mesenchymal cells, and GPCRs.
The downstream signaling cascades involve several isoforms of phospholipases
PLC-epsilon) which catalyze hydrolysis of
PI(4,5)P2 (phosphatidylinositol-4,5-biphosphate) into
IP3 and DAG, Upon its release
to cytoplasm, IP3 binds to IP3R (IP3 Receptor) on the
surface of Endoplasmic Reticulum and mobilizes Ca(II) from
internal stores .
B-cell antigen receptor (BCR) is the multiprotein complex composed of Membrane
Immunoglobulin molecules and associated
Ig-Alpha(CD79A)/Ig-Beta(CD79B) heterodimer .
The Membrane Immunoglobulin subunits bind antigens and cause receptor aggregation, while
CD79A/CD79B subunits transduce signals to the cell interior.
BCR activates protein tyrosine kinase Syk, which, in turn,
phosphorylates phospholipase PLC-gamma .
PLC-beta is activated by G-proteins, such as
G-proteins alpha-q/11 and G-proteins
beta/gamma, which, in turn, are activated by GPCRs, such as
Gqa specific GPCR , .
T cell receptor (TCR-CD3 complex) transduces signals to
the protein kinase ZAP70, which further phosphorylates
transmembrane adaptor LAT . LAT
activates PLC-gamma .
PDGFR (platelet-derived growth factor receptor) induces
cascade which activates PLC-epsilon , .
Phospholipase-induced Ca(II) release into cytoplasm
Ca(II)/calmodulin complex binds
to and stimulates Ca(II)/calmodulin-dependent protein kinases
CaMKK, CaMKII and
CaMKIV. CaMKIV is also
activated through phosphorylation by the upstream CaMKK
cascade then stimulates transcription by phosphorylation of several
transcription factors, such as CREB and
MEF2, and, at the same time, inhibits the activity of
histone deacetylases that belong to class II (HDAC4/5/7)
DAG activates several isoforms of Protein kinase C
(PKC), which stimulate v-raf-1 murine leukemia viral
oncogene homolog 1 (c-RAF-1)  and initiate
Mitogen-activated protein kinase kinases 1 and 2 (MEK1
and MEK2)/ Mitogen-activated protein kinases 3 and 1
(ERK1 and ERK2) cascade that,
in turn, activates several transcription factors including
ELK1. ELK1 forms an important
link in the MAP kinase pathway to transduce signals from the cell surface to the nucleus
to activate genetic machinery necessary for the maintenance of synaptic plasticity
PI(4,5)P2 is converted into PI(3,4,5)P3
by the Phosphoinositide-3 kinase (PIK3).
PI(3,4,5)P3 is a second messenger that activates diverse
intracellular pathways, e.g.
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