Signal transduction IP3 signaling
IP3 signaling
Efficient and coordinated synthesis of the second messengers, includingInositol-1,4,5-trisphosphate (IP3 ), Diacylglycerol ( DAG ), andPhosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3 ), is necessary for normalcell functioning. Production of secondary messengers is regulated by a variety ofmembrane receptors and downstream signaling cascades.
IP3 signaling is initiated by its binding to cognate receptors, such as B-cellantigen 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-beta, PLC-gamma, PLC-epsilon ) which catalyze hydrolysis ofPI(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 ofEndoplasmic Reticulum and mobilizes Ca(II) from internal stores [1].
B-cell antigen receptor (BCR) is the multiprotein complex composed of MembraneImmunoglobulin molecules and associated Ig-Alpha ( CD79A )/Ig-Beta (CD79B)heterodimer [2]. The Membrane Immunoglobulin subunits bind antigens andcause receptor aggregation, while CD79A/CD79B subunits transduce signals to thecell interior. BCR activates protein tyrosine kinase Syk, which, in turn,phosphorylates p hospholipase PLC-gamma [3].
PLC-beta is activated by G-proteins, such as G-proteins alpha-q/11 andG-proteins beta/gamma, which, in turn, are activated by GPCRs, such as Gqaspecific GPCR [4], [5].
T cell receptor ( TCR-CD3 complex ) transduces signals to the protein kinaseZAP70, which further phosphorylates transmembrane adaptor LAT [6]. LAT activates PLC-gamma [7].
PDGFR (platelet-derived growth factor receptor) induces Shc/Grb2/ SOS/ H-RAS cascade which activates PLC-epsilon [8], [9].
P hospholipase-induced Ca(II) release into cytoplasm activatescalmodulin. Ca(II)/ calmodulin complex binds to and stimulatesCa(II)/calmodulin-dependent protein kinases CaMKK, CaMKII andCaMKIV. CaMKIV is also activated through phosphorylation by the upstreamCaMKK [10]. CaMKK/ CaMKIV cascade then stimulatestranscription by phosphorylation of several transcription factors, such as CREBand MEF2, and, at the same time, inhibits the activity of histone deacetylasesthat belong to class II ( HDAC4/5/7 ) [11].
DAG activates several isoforms of Protein kinase C ( PKC ), whichstimulate v-raf-1 murine leukemia viral oncogene homolog 1 ( c-RAF-1 ) [12] and initiate Mitogen-activated protein kinase kinases 1 and 2 ( MEK1 andMEK2 )/ 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 fromthe cell surface to the nucleus to activate genetic machinery necessary for themaintenance of synaptic plasticity [13].
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 diverseintracellular pathway s, e.g. PDK/ AKT signaling.
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