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) , .
One of important Endothelin-1/
EDNRA-induced signal pathways is Epidermal growth factor
receptor (EGFR) transactivation , , . This pathway may participate in regulation of cell growth,
contractility and fibrogenesis in the vascular and muscular tissues , , .
EDNRA is a G-protein coupled receptor . Endothelin-1/
transactivation is likely realized via G-protein alpha-q/11
. 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) , . DAG and IP3 stimulate
Protein kinase C, delta (PKC-delta) and mobilize
intracellular Ca('2+), respectively .
Activated PKC-delta stimulates
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
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 .
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 , , .
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) , , .
In addition, ERK1/2 may stimulate expression of
transcription factor v-fos FBJ murine osteosarcoma viral oncogene homolog
(c-Fos)  (e.g., via
SP1), thus activating cell growth and proliferation.
Moreover, ERK1/2 activated via
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 .
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)) . 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 , . Thus,
pathway may participate in progression of cell cycle and translation.
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