Development - Endothelin-1/EDNRA transactivation of EGFR

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 [4], [5], [6].

EDNRA is a G-protein coupled receptor [7]. Endothelin-1/ EDNRA-induced EGFR transactivation is likely realized via G-protein alpha-q/11 [8]. After ENDRA stimulation by Endothelin-1, G-protein alpha-q/11 dissociates from complex with beta\gamma 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.

References:

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