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Development Endothelin-1/EDNRA signaling


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Development Endothelin-1/EDNRA signaling

Endothelin-1 signaling via EDNRA

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

EDNRA belongs to the superfamily of rhodopsin-like proteins comprising seventransmembrane-spanning regions. These proteins are involved in intracellular signalingpathways through activation of associated guanine nucleotide binding proteins(G-proteins). EDNRA is bound with G-protein alpha-s, G-proteinalpha-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-proteinalpha-s and, thus, enhances intracellular concentration of Cyclic AMP (cAMP ) [5], [2], [6].

Other G-proteins, G-protein alpha-q/11 and G-protein alpha-i family, after ENDRA stimulation by Endothelin-1 dissociate from complex withbeta\gamma subunits, and activate any Phospholipase C beta (PLC-beta), e.g. PhospholipaseC beta 3 ( PLC-beta3 ). PLC-beta3 hydrolyses of Phosphatidylinositol4,5-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, deltaand epsilon ( PKC-delta and PKC-epsilon ) and mobilize intracellularCa('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 proteintyrosine kinase 2 beta ( Pyk2(FAK2) )/ v-src sarcoma (Schmidt-Ruppin A-2) viraloncogene homolog ( c-Src ) complex [11], [12].

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

For example, c-Src phosphorylates SHC (Src homology 2 domain containing)transforming protein 1 ( Shc ). It leads to activation of Growth factorreceptor-bound protein 2 ( Grb2 )/ Son of sevenless homologs ( Sos )complex. Sos catalyzes conversion of v-Ha-ras Harvey rat sarcoma viral oncogenehomolog ( H-Ras ) from GDP- to GTP-form. H-Ras -GTP is then binds to andactivates v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) andMEK2(MAP2K2) )/ Mitogen activated protein kinases 3 and 1 ( ERK1/2 )[11], [12].

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

On the other hand, Endothelin-1/ EDNRA -activated c-Src mayphosphorylate guanine-nucleotide exchange factor FERM, RhoGEF and pleckstrin domainprotein 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-activatedprotein kinases 8-10 ( JNK(MAPK8-10) ) cascade. This pathway leads to inhibitionof 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 oncogenehomolog 1 ( AKT(PKB) ). A ctivation of AKT(PKB) leads to matrix contraction[17]. In addition, activation of the PI3K/ AKT(PKB) inhibitsGlycogen synthase kinase 3 beta ( GSK-3beta ) by phosphorylation, which, in turn,leads to stabilization of the active soluble form of Catenin (cadherin-associatedprotein), beta 1 (Beta-catenin). Beta-catenin activates Transcriptionfactor 7-like 2 ( TCF-4 ), which activates transcription of Cyclin D1.Moreover, Beta-catenin/ TCF-4 enhances Endothelin-1 promoter activity in areciprocal manner. Activation of the Beta-catenin/ TCF-4 cascade byEndothelin-1 results in the proliferation and inhibits apoptosis [18].

Moreover, c-Src may activate Mitogen-activated protein kinase kinase kinase 4MEKK4(MAP3K4)/ Mitogen-activated protein kinase kinase 6 ( MEK6(MAP2K6 ))/Mitogen-activated protein kinases 14 ( p38alpha(MAPK14) ) cascade [19],[20] 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 cardiachypertrophic protein BNP [15], [21].