Signal transduction - IP3 signaling

IP3 signaling

Efficient and coordinated synthesis of the second messengers, including Inositol-1,4,5-trisphosphate (IP3), Diacylglycerol (DAG), and 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-beta, PLC-gamma, 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 [1].

B-cell antigen receptor (BCR) is the multiprotein complex composed of Membrane Immunoglobulin molecules and associated Ig-Alpha(CD79A)/Ig-Beta(CD79B) heterodimer [2]. 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 [3].

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 [4], [5].

T cell receptor (TCR-CD3 complex) transduces signals to the protein kinase ZAP70, 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].

Phospholipase-induced Ca(II) release into cytoplasm activates calmodulin. 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 [10]. CaMKK/CaMKIV 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) [11].

DAG activates several isoforms of Protein kinase C (PKC), which stimulate v-raf-1 murine leukemia viral oncogene homolog 1 (c-RAF-1) [12] 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 [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 diverse intracellular pathways, e.g. PDK/AKT signaling.

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