Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
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Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

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].