Development - Endothelin-1/EDNRA signaling

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:

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