Signal transduction - IP3 signaling

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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.

References:

  1. Katan M
    The control of inositol lipid hydrolysis. Cancer surveys 1996;27:199-211
  2. Geisberger R, Crameri R, Achatz G
    Models of signal transduction through the B-cell antigen receptor. Immunology 2003 Dec;110(4):401-10
  3. Pao LI, Cambier JC
    Syk, but not Lyn, recruitment to B cell antigen receptor and activation following stimulation of CD45- B cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Mar 15;158(6):2663-9
  4. Rhee SG
    Regulation of phosphoinositide-specific phospholipase C. Annual review of biochemistry 2001;70:281-312
  5. Wettschureck N, Offermanns S
    Mammalian G proteins and their cell type specific functions. Physiological reviews 2005 Oct;85(4):1159-204
  6. Chan AC, Desai DM, Weiss A
    The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Annual review of immunology 1994;12:555-92
  7. Wilson BS, Pfeiffer JR, Surviladze Z, Gaudet EA, Oliver JM
    High resolution mapping of mast cell membranes reveals primary and secondary domains of Fc(epsilon)RI and LAT. The Journal of cell biology 2001 Aug 6;154(3):645-58
  8. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  9. Wing MR, Snyder JT, Sondek J, Harden TK
    Direct activation of phospholipase C-epsilon by Rho. The Journal of biological chemistry 2003 Oct 17;278(42):41253-8
  10. Tokumitsu H, Takahashi N, Eto K, Yano S, Soderling TR, Muramatsu M
    Substrate recognition by Ca2+/Calmodulin-dependent protein kinase kinase. Role of the arg-pro-rich insert domain. The Journal of biological chemistry 1999 May 28;274(22):15803-10
  11. Tombal B, Weeraratna AT, Denmeade SR, Isaacs JT
    Thapsigargin induces a calmodulin/calcineurin-dependent apoptotic cascade responsible for the death of prostatic cancer cells. The Prostate 2000 Jun 1;43(4):303-17
  12. Marais R, Light Y, Mason C, Paterson H, Olson MF, Marshall CJ
    Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C. Science (New York, N.Y.) 1998 Apr 3;280(5360):109-12
  13. Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S
    The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 2000 Jun 15;20(12):4563-72

  1. Katan M
    The control of inositol lipid hydrolysis. Cancer surveys 1996;27:199-211
  2. Geisberger R, Crameri R, Achatz G
    Models of signal transduction through the B-cell antigen receptor. Immunology 2003 Dec;110(4):401-10
  3. Pao LI, Cambier JC
    Syk, but not Lyn, recruitment to B cell antigen receptor and activation following stimulation of CD45- B cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Mar 15;158(6):2663-9
  4. Rhee SG
    Regulation of phosphoinositide-specific phospholipase C. Annual review of biochemistry 2001;70:281-312
  5. Wettschureck N, Offermanns S
    Mammalian G proteins and their cell type specific functions. Physiological reviews 2005 Oct;85(4):1159-204
  6. Chan AC, Desai DM, Weiss A
    The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Annual review of immunology 1994;12:555-92
  7. Wilson BS, Pfeiffer JR, Surviladze Z, Gaudet EA, Oliver JM
    High resolution mapping of mast cell membranes reveals primary and secondary domains of Fc(epsilon)RI and LAT. The Journal of cell biology 2001 Aug 6;154(3):645-58
  8. Lin J, Weiss A
    T cell receptor signalling. Journal of cell science 2001 Jan;114(Pt 2):243-4
  9. Wing MR, Snyder JT, Sondek J, Harden TK
    Direct activation of phospholipase C-epsilon by Rho. The Journal of biological chemistry 2003 Oct 17;278(42):41253-8
  10. Tokumitsu H, Takahashi N, Eto K, Yano S, Soderling TR, Muramatsu M
    Substrate recognition by Ca2+/Calmodulin-dependent protein kinase kinase. Role of the arg-pro-rich insert domain. The Journal of biological chemistry 1999 May 28;274(22):15803-10
  11. Tombal B, Weeraratna AT, Denmeade SR, Isaacs JT
    Thapsigargin induces a calmodulin/calcineurin-dependent apoptotic cascade responsible for the death of prostatic cancer cells. The Prostate 2000 Jun 1;43(4):303-17
  12. Marais R, Light Y, Mason C, Paterson H, Olson MF, Marshall CJ
    Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C. Science (New York, N.Y.) 1998 Apr 3;280(5360):109-12
  13. Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S
    The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 2000 Jun 15;20(12):4563-72

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