Development - Endothelin-1/EDNRA signaling

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Endothelin-1 signaling via EDNRA

Endothelin-1, a potent endothelium-derived vasoconstrictor peptide, exerts a growth-promoting effect on vascular smooth muscle cells, implicating its pathogenic role in vascular remodeling. Endothelin-1 action is exerted by its binding to Endothelin receptor type A (EDNRA) [1].

EDNRA belongs to the superfamily of rhodopsin-like proteins comprising seven transmembrane-spanning regions. These proteins are involved in intracellular signaling pathways through activation of associated guanine nucleotide binding proteins (G-proteins). EDNRA is bound with G-protein alpha-s, G-protein alpha-q/11 and G-protein alpha-i family [2], [3], [4]. The exact G-proteins and signaling cascades are not known.

EDNRA probably activates Adenylate cyclase via G-protein alpha-s and, thus, enhances intracellular concentration of Cyclic AMP (cAMP) [2], [5], [6].

Other G-proteins, G-protein alpha-q/11 and G-protein alpha-i family, after ENDRA stimulation by Endothelin-1 dissociate from complex with beta\gamma subunits, and activate any Phospholipase C beta (PLC-beta), e.g. Phospholipase C beta 3 (PLC-beta3). PLC-beta3 hydrolyses of Phosphatidylinositol 4,5-bisphosphate (Ptdins(4,5)P2) and the generation of Diacylglycerol (DAG) and Inositol trisphosphate (IP3) [7], [8], [9]. DAG and IP3 stimulate Protein kinase C, delta and epsilon (PKC-delta and PKC-epsilon) and mobilize intracellular Ca('2+), respectively [10], [11], [12], [13].

PKC-delta, PKC-epsilon and Ca2+ (via intermediate, presumably - Calcium/calmodulin-dependent protein kinase II (CaMK II)) activate PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2))/ v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (c-Src) complex [11], [12].

G-protein alpha-s and G-protein alpha-i may activate c-Src directly [14]. Many Endothelin-1-induced cascades may be activated via c-Src.

For example, c-Src phosphorylates SHC (Src homology 2 domain containing) transforming protein 1 (Shc). It leads to activation of Growth factor receptor-bound protein 2 (Grb2)/ Son of sevenless homologs (Sos) complex. Sos catalyzes conversion of v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) from GDP- to GTP-form. H-Ras-GTP is then binds to and activates v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) and MEK2(MAP2K2))/ Mitogen activated protein kinases 3 and 1 (ERK1/2) [11], [12].

Endothelin-1/ EDNRA-dependent ERK1/2 may stimulate any translation factor (e.g., ELK1, member of ETS oncogene family (Elk-1)), which, in turn, activates transcription of cardiac hypertrophic protein Natriuretic peptide precursor B (BNP) [15]. In addition, ERK1/2 activation leads to cell proliferation [11], [12].

On the other hand, Endothelin-1/ EDNRA-activated c-Src may phosphorylate guanine-nucleotide exchange factor FERM, RhoGEF and pleckstrin domain protein 2 (FARP2). FARP2 activates Cell division cycle 42 (CDC42)/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1))/ Mitogen-activated protein kinase kinase 4 (MEK4(MAP2K4))/ Mitogen-activated protein kinases 8-10 (JNK(MAPK8-10)) cascade. This pathway leads to inhibition of cell motility [16].

An unknown c-Src-activated guanine-nucleotide exchange factor (e.g., FARP2) stimulates Ras-related C3 botulinum toxin substrate 1 (Rac1)/ phosphatidylinositol 3 kinase (PI3K)/ v-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)). Activation of AKT(PKB) leads to matrix contraction [17]. In addition, activation of the PI3K/ AKT(PKB) inhibits Glycogen synthase kinase 3 beta (GSK-3beta) by phosphorylation, which, in turn, leads to stabilization of the active soluble form of Catenin (cadherin-associated protein), beta 1 (Beta-catenin). Beta-catenin activates Transcription factor 7-like 2 (TCF-4), which activates transcription of Cyclin D1. Moreover, Beta-catenin/ TCF-4 enhances Endothelin-1 promoter activity in a reciprocal manner. Activation of the Beta-catenin/ TCF-4 cascade by Endothelin-1 results in the proliferation and inhibits apoptosis [18].

Moreover, c-Src may activate Mitogen-activated protein kinase kinase kinase 4 MEKK4(MAP3K4)/ Mitogen-activated protein kinase kinase 6 (MEK6(MAP2K6))/ Mitogen-activated protein kinases 14 (p38alpha(MAPK14)) cascade {PMID: 9679149}, [19] via some small GTP binding proteins (e.g., CDC42). p38alpha(MAPK14) stimulate by phosphorylation GATA binding protein 4 (GATA-4), and Elk-1 which in turn activates transcription of cardiac hypertrophic protein BNP [15], [20].

References:

  1. Kedzierski RM, Yanagisawa M
    Endothelin system: the double-edged sword in health and disease. Annual review of pharmacology and toxicology 2001;41:851-76
  2. Takigawa M, Sakurai T, Kasuya Y, Abe Y, Masaki T, Goto K
    Molecular identification of guanine-nucleotide-binding regulatory proteins which couple to endothelin receptors. European journal of biochemistry / FEBS 1995 Feb 15;228(1):102-8
  3. Shraga-Levine Z, Sokolovsky M
    Functional coupling of G proteins to endothelin receptors is ligand and receptor subtype specific. Cellular and molecular neurobiology 2000 Jun;20(3):305-17
  4. Cramer H, Schmenger K, Heinrich K, Horstmeyer A, Boning H, Breit A, Piiper A, Lundstrom K, Muller-Esterl W, Schroeder C
    Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and G(alpha)q. European journal of biochemistry / FEBS 2001 Oct;268(20):5449-59
  5. Aramori I, Nakanishi S
    Coupling of two endothelin receptor subtypes to differing signal transduction in transfected Chinese hamster ovary cells. The Journal of biological chemistry 1992 Jun 25;267(18):12468-74
  6. Imokawa G, Yada Y, Kimura M
    Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes. The Biochemical journal 1996 Feb 15;314 ( Pt 1):305-12
  7. Matsumoto S, Yorio T, Magnino PE, DeSantis L, Pang IH
    Endothelin-induced changes of second messengers in cultured human ciliary muscle cells. Investigative ophthalmology & visual science 1996 May;37(6):1058-66
  8. Haque MS, Pang IH, Magnino PE, DeSantis L
    Activation of phospholipase C and guanylyl cyclase by endothelins in human trabecular meshwork cells. Current eye research 1998 Dec;17(12):1110-7
  9. Kleeberg J, Petzold GC, Major S, Dirnagl U, Dreier JP
    ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. American journal of physiology. Heart and circulatory physiology 2004 Apr;286(4):H1339-46
  10. Clerk A, Bogoyevitch MA, Anderson MB, Sugden PH
    Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. The Journal of biological chemistry 1994 Dec 30;269(52):32848-57
  11. Robin P, Boulven I, Desmyter C, Harbon S, Leiber D
    ET-1 stimulates ERK signaling pathway through sequential activation of PKC and Src in rat myometrial cells. American journal of physiology. Cell physiology 2002 Jul;283(1):C251-60
  12. Robin P, Boulven I, Bole-Feysot C, Tanfin Z, Leiber D
    Contribution of PKC-dependent and -independent processes in temporal ERK regulation by ET-1, PDGF, and EGF in rat myometrial cells. American journal of physiology. Cell physiology 2004 Apr;286(4):C798-806
  13. Chintalgattu V, Katwa LC
    Role of protein kinase Cdelta in endothelin-induced type I collagen expression in cardiac myofibroblasts isolated from the site of myocardial infarction. The Journal of pharmacology and experimental therapeutics 2004 Nov;311(2):691-9
  14. Ma YC, Huang XY
    Novel regulation and function of Src tyrosine kinase. Cellular and molecular life sciences : CMLS 2002 Mar;59(3):456-62
  15. Kerkela R, Pikkarainen S, Majalahti-Palviainen T, Tokola H, Ruskoaho H
    Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene. The Journal of biological chemistry 2002 Apr 19;277(16):13752-60
  16. Miyamoto Y, Yamauchi J, Itoh H
    Src kinase regulates the activation of a novel FGD-1-related Cdc42 guanine nucleotide exchange factor in the signaling pathway from the endothelin A receptor to JNK. The Journal of biological chemistry 2003 Aug 8;278(32):29890-900
  17. Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou-Gharios G, Pearson JD, Dashwood M, du Bois RM, Black CM, Leask A, Abraham DJ
    Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Molecular biology of the cell 2004 Jun;15(6):2707-19
  18. Sun P, Xiong H, Kim TH, Ren B, Zhang Z
    Positive inter-regulation between beta-catenin/T cell factor-4 signaling and endothelin-1 signaling potentiates proliferation and survival of prostate cancer cells. Molecular pharmacology 2006 Feb;69(2):520-31
  19. Sorokin A, Kozlowski P, Graves L, Philip A
    Protein-tyrosine kinase Pyk2 mediates endothelin-induced p38 MAPK activation in glomerular mesangial cells. The Journal of biological chemistry 2001 Jun 15;276(24):21521-8
  20. Pikkarainen S, Tokola H, Kerkela R, Majalahti-Palviainen T, Vuolteenaho O, Ruskoaho H
    Endothelin-1-specific activation of B-type natriuretic peptide gene via p38 mitogen-activated protein kinase and nuclear ETS factors. The Journal of biological chemistry 2003 Feb 7;278(6):3969-75

  1. Kedzierski RM, Yanagisawa M
    Endothelin system: the double-edged sword in health and disease. Annual review of pharmacology and toxicology 2001;41:851-76
  2. Takigawa M, Sakurai T, Kasuya Y, Abe Y, Masaki T, Goto K
    Molecular identification of guanine-nucleotide-binding regulatory proteins which couple to endothelin receptors. European journal of biochemistry / FEBS 1995 Feb 15;228(1):102-8
  3. Shraga-Levine Z, Sokolovsky M
    Functional coupling of G proteins to endothelin receptors is ligand and receptor subtype specific. Cellular and molecular neurobiology 2000 Jun;20(3):305-17
  4. Cramer H, Schmenger K, Heinrich K, Horstmeyer A, Boning H, Breit A, Piiper A, Lundstrom K, Muller-Esterl W, Schroeder C
    Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and G(alpha)q. European journal of biochemistry / FEBS 2001 Oct;268(20):5449-59
  5. Aramori I, Nakanishi S
    Coupling of two endothelin receptor subtypes to differing signal transduction in transfected Chinese hamster ovary cells. The Journal of biological chemistry 1992 Jun 25;267(18):12468-74
  6. Imokawa G, Yada Y, Kimura M
    Signalling mechanisms of endothelin-induced mitogenesis and melanogenesis in human melanocytes. The Biochemical journal 1996 Feb 15;314 ( Pt 1):305-12
  7. Matsumoto S, Yorio T, Magnino PE, DeSantis L, Pang IH
    Endothelin-induced changes of second messengers in cultured human ciliary muscle cells. Investigative ophthalmology & visual science 1996 May;37(6):1058-66
  8. Haque MS, Pang IH, Magnino PE, DeSantis L
    Activation of phospholipase C and guanylyl cyclase by endothelins in human trabecular meshwork cells. Current eye research 1998 Dec;17(12):1110-7
  9. Kleeberg J, Petzold GC, Major S, Dirnagl U, Dreier JP
    ET-1 induces cortical spreading depression via activation of the ETA receptor/phospholipase C pathway in vivo. American journal of physiology. Heart and circulatory physiology 2004 Apr;286(4):H1339-46
  10. Clerk A, Bogoyevitch MA, Anderson MB, Sugden PH
    Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. The Journal of biological chemistry 1994 Dec 30;269(52):32848-57
  11. Robin P, Boulven I, Desmyter C, Harbon S, Leiber D
    ET-1 stimulates ERK signaling pathway through sequential activation of PKC and Src in rat myometrial cells. American journal of physiology. Cell physiology 2002 Jul;283(1):C251-60
  12. Robin P, Boulven I, Bole-Feysot C, Tanfin Z, Leiber D
    Contribution of PKC-dependent and -independent processes in temporal ERK regulation by ET-1, PDGF, and EGF in rat myometrial cells. American journal of physiology. Cell physiology 2004 Apr;286(4):C798-806
  13. Chintalgattu V, Katwa LC
    Role of protein kinase Cdelta in endothelin-induced type I collagen expression in cardiac myofibroblasts isolated from the site of myocardial infarction. The Journal of pharmacology and experimental therapeutics 2004 Nov;311(2):691-9
  14. Ma YC, Huang XY
    Novel regulation and function of Src tyrosine kinase. Cellular and molecular life sciences : CMLS 2002 Mar;59(3):456-62
  15. Kerkela R, Pikkarainen S, Majalahti-Palviainen T, Tokola H, Ruskoaho H
    Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene. The Journal of biological chemistry 2002 Apr 19;277(16):13752-60
  16. Miyamoto Y, Yamauchi J, Itoh H
    Src kinase regulates the activation of a novel FGD-1-related Cdc42 guanine nucleotide exchange factor in the signaling pathway from the endothelin A receptor to JNK. The Journal of biological chemistry 2003 Aug 8;278(32):29890-900
  17. Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou-Gharios G, Pearson JD, Dashwood M, du Bois RM, Black CM, Leask A, Abraham DJ
    Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Molecular biology of the cell 2004 Jun;15(6):2707-19
  18. Sun P, Xiong H, Kim TH, Ren B, Zhang Z
    Positive inter-regulation between beta-catenin/T cell factor-4 signaling and endothelin-1 signaling potentiates proliferation and survival of prostate cancer cells. Molecular pharmacology 2006 Feb;69(2):520-31
  19. Sorokin A, Kozlowski P, Graves L, Philip A
    Protein-tyrosine kinase Pyk2 mediates endothelin-induced p38 MAPK activation in glomerular mesangial cells. The Journal of biological chemistry 2001 Jun 15;276(24):21521-8
  20. Pikkarainen S, Tokola H, Kerkela R, Majalahti-Palviainen T, Vuolteenaho O, Ruskoaho H
    Endothelin-1-specific activation of B-type natriuretic peptide gene via p38 mitogen-activated protein kinase and nuclear ETS factors. The Journal of biological chemistry 2003 Feb 7;278(6):3969-75

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