Pathway Map Details

Development_Endothelin-1/EDNRA transactivation of EGFR



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ADAM9, PI3K reg class IA, Ca('2+) = Ca('2+), Collagen I, L-type Ca(II) channel, alpha 1C subunit, PKC-delta, PtdIns(3,4,5)P3, EDNRA, IP3 receptor, H(,2)O + 1-(1,2-diacyl-glycerol 3-phospho)-inositol 4,5-bisphosphate = 1,2-diacyl-glycerol + inositol 1,4,5-trisphosphate, EGFR, p70 S6 kinase1, Ca('2) cytosol, HB-EGF, p70 S6 kinase2, c-Src, PLC-beta, DAG, MEK1(MAP2K1), MEK2(MAP2K2), SP1, Endothelin-1, Erk (MAPK1/3), Pyk2(FAK2), 2.7.1.153, GRB2, H-Ras, AKT(PKB), Shc, Ca('2+) = Ca('2+), c-Raf-1, Calmodulin, Ca('2+) endoplasmic reticulum, IP3, CaMK II, c-Fos, STAT5, SOS, PtdIns(4,5)P2, RHEB2, mTOR, PDK (PDPK1), G-protein alpha-q/11, Ca('2+) extracellular region, Tuberin, PI3K cat class IA

Description:

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 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:

  1. Kedzierski RM, Yanagisawa M
    Endothelin system: the double-edged sword in health and disease. Annual review of pharmacology and toxicology 2001;41:851-76
  2. Iwasaki H, Eguchi S, Ueno H, Marumo F, Hirata Y
    Endothelin-mediated vascular growth requires p42/p44 mitogen-activated protein kinase and p70 S6 kinase cascades via transactivation of epidermal growth factor receptor. Endocrinology 1999 Oct;140(10):4659-68
  3. Robin P, Boulven I, Desmyter C, Harbon S, Leiber D
    ET-1 stimulates ERK signaling pathway through sequential activation of PKC and Src in rat myometrial cells. American journal of physiology. Cell physiology. 2002 Jul;283(1):C251-60
  4. Chansel D, Ciroldi M, Vandermeersch S, Jackson LF, Gomez AM, Henrion D, Lee DC, Coffman TM, Richard S, Dussaule JC, Tharaux PL
    Heparin binding EGF is necessary for vasospastic response to endothelin. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2006 Sep;20(11):1936-8
  5. Flamant M, Tharaux PL, Placier S, Henrion D, Coffman T, Chatziantoniou C, Dussaule JC
    Epidermal growth factor receptor trans-activation mediates the tonic and fibrogenic effects of endothelin in the aortic wall of transgenic mice. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Feb;17(2):327-9
  6. Chintalgattu V, Katwa LC
    Role of protein kinase Cdelta in endothelin-induced type I collagen expression in cardiac myofibroblasts isolated from the site of myocardial infarction. The Journal of pharmacology and experimental therapeutics 2004 Nov;311(2):691-9
  7. Davenport AP
    International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature. Pharmacological reviews 2002 Jun;54(2):219-26
  8. Kodama H, Fukuda K, Takahashi T, Sano M, Kato T, Tahara S, Hakuno D, Sato T, Manabe T, Konishi F, Ogawa S
    Role of EGF Receptor and Pyk2 in endothelin-1-induced ERK activation in rat cardiomyocytes. Journal of molecular and cellular cardiology 2002 Feb;34(2):139-50
  9. Matsumoto S, Yorio T, Magnino PE, DeSantis L, Pang IH
    Endothelin-induced changes of second messengers in cultured human ciliary muscle cells. Investigative ophthalmology & visual science 1996 May;37(6):1058-66
  10. Haque MS, Pang IH, Magnino PE, DeSantis L
    Activation of phospholipase C and guanylyl cyclase by endothelins in human trabecular meshwork cells. Current eye research 1998 Dec;17(12):1110-7
  11. Vacca F, Bagnato A, Catt KJ, Tecce R
    Transactivation of the epidermal growth factor receptor in endothelin-1-induced mitogenic signaling in human ovarian carcinoma cells. Cancer research 2000 Sep 15;60(18):5310-7
  12. Bagnato A, Spinella F, Rosano L
    Emerging role of the endothelin axis in ovarian tumor progression. Endocrine-related cancer 2005 Dec;12(4):761-72
  13. Boerner JL, Biscardi JS, Silva CM, Parsons SJ
    Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis. Molecular carcinogenesis 2005 Dec;44(4):262-73
  14. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J
    Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Current biology : CB 2003 Aug 5;13(15):1259-68