Pathway maps

Endothelin-1/EDNRA signaling via EGFR

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 initiated by its binding to Endothelin receptor type A ( EDNRA ) [1], [2].

One of important Endothelin-1/ EDNRA -induced signal pathways is Epidermal growth factor receptor ( EGFR ) transactivation [2], [3], [4]. This pathway may participate in regulation of cell growth, contractility and fibrogenesis in the vascular and muscular tissues [5], [6], [4].

EDNRA is a G-protein coupled receptor [7]. Endothelin-1/ EDNRA -induced EGFR transactivation is likely realized via G-protein alpha-q/11 [8]. A fter ENDRA stimulation by Endothelin-1, G-protein alpha-q/11 dissociates from complex with betagamma subunits, and activate Phospholipase C beta ( PLC beta ). PLC beta catalyzes hydrolysis of phosphatidylinositol 4,5-bisphosphate ( Ptdins(4,5)P2 ) and the generation of diacylglycerol ( DAG ) and inositol trisphosphate ( IP3 ) [9], [10]. DAG and IP3 stimulate Protein kinase C, delta ( PKC-delta ) and mobilize intracellular Ca('2+), respectively [6].

Activated PKC-delta stimulates Ca('2+) -independent pathway EGFR transactivation. PKC-delta induces Heparin-binding EGF-like growth factor ( HB-EGF ) via cleavage of pro- HB-EGF by matrix metalloproteinase (e.g., ADAM metallopeptidase domain 9 ( ADAM9 )) and the subsequent release of HB-EGF, which, in turn, binds to EGFR, leading to EGFR activation [8].

In addition, PKC-delta and Ca('2+) (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. c-Src phosphorylates EGFR, thus realizing Ca('2+) -dependent pathway EGFR transactivation [2].

The activated EGFR provides binding sites for cellular proteins containing Src homology-2 domain of adaptor proteins, such as SHC (Src homology 2 domain containing) transforming protein 1 ( Shc ) and Growth factor receptor-bound protein 2 ( GRB2 ). Both EGFR and Shc are tyrosine phosphorylated by c-Src. Then EGFR and Shc are bound to each other as well as Grb2/ Son of sevenless homologs ( Sos ) complex. Sos catalyzes o conversion of v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) from GDP- to GTP-form. H-Ras -GTP is then able to bind to and activate 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) ) cascade [2], [11], [12].

Endothelin-1/ EDNRA/ EGFR -activated ERK1/2 participates in remodeling/fibrosis of vascular and muscular tissues (possibly, via activator of transcription Collagen I via Signal transducer and activator of transcription 5 ( STAT5 )/ Sp1 transcription factor ( SP1 ) [5], [6], [13].

In addition, ERK1/2 may stimulate expression of transcription factor v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [8] (e.g., via SP1 ), thus activating cell growth and proliferation.

Moreover, ERK1/2 activated via Endothelin-1/ EDNRA Ca('2+) -dependent EGFR transactivation, may phosphorylate Ribosomal protein S6 kinase, 70kDa, polypeptide 2 ( p70 S6 kinase 2), which plays a critical role in progression of cell cycle and translation [2].

Endothelin-1/ EDNRA -induced EGFR activates Phosphatidylinositol 3 kinase ( PI3K )/ v-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ) pathway. PI3K/ AKT(PKB) may stimulate Ca('2+) uptake (e.g., via Calcium channels, voltage-dependent, L type ( L-type Ca(II) channel )) [4]. In addition, PI3K/ AKT(PKB) pathway may stimulate FK506 binding protein 12-rapamycin associated protein 1 ( mTOR ), which activates Ribosomal protein S6 kinase, 70kDa, polypeptide 1 ( p70 S6 kinases 1 ) and p70 S6 kinase 2 [2], [14]. Thus, PI3K/ AKT(PKB) pathway may participate in progression of cell cycle and translation.