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Development Endothelin-1/EDNRA transactivation of EGFR

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Development Endothelin-1/EDNRA transactivation of EGFR

Endothelin-1/EDNRA signaling via EGFR

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

One of important Endothelin-1/ EDNRA -induced signal pathways isEpidermal 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-proteinalpha-q/11 [8]. A fter ENDRA stimulation by Endothelin-1,G-protein alpha-q/11 dissociates from complex with beta\gamma subunits, and activatePhospholipase C beta ( PLC beta ). PLC beta catalyzes hydrolysis ofphosphatidylinositol 4,5-bisphosphate ( Ptdins(4,5)P2 ) and the generation ofdiacylglycerol ( 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 EGFRtransactivation. 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 ofHB-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 proteintyrosine kinase 2 beta ( Pyk2(FAK2) )/ v-src sarcoma (Schmidt-Ruppin A-2) viraloncogene homolog ( c-Src ) complex. c-Src phosphorylates EGFR, thusrealizing Ca('2+) -dependent pathway EGFR transactivation [2].

The activated EGFR provides binding sites for cellular proteins containing Srchomology-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 byc-Src. Then EGFR and Shc are bound to each other as well asGrb2/ Son of sevenless homologs ( Sos ) complex. Sos catalyzes oconversion of v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) fromGDP- to GTP-form. H-Ras -GTP is then able to bind to and activate v-raf-1 murineleukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinasekinases 1 and 2 ( MEK1(MAP2K1) and MEK2(MAP2K2) )/ Mitogen activatedprotein kinases 3 and 1 ( ERK1/2) ) cascade [2], [11],[12].

Endothelin-1/ EDNRA/ EGFR -activated ERK1/2 participatesin remodeling/fibrosis of vascular and muscular tissues (possibly, via activator oftranscription 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 FBJmurine osteosarcoma viral oncogene homolog ( c-Fos ) [8] (e.g., viaSP1 ), thus activating cell growth and proliferation.

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

Endothelin-1/ EDNRA -induced EGFR activates Phosphatidylinositol3 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 maystimulate FK506 binding protein 12-rapamycin associated protein 1 ( mTOR ), whichactivates 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.