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Molecular Pharmacology

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Research ArticleArticle

Agonist-Induced Interactions between Angiotensin AT1 and Epidermal Growth Factor Receptors

J. Alberto Olivares-Reyes, Bukhtiar H. Shah, Judith Hernández-Aranda, Agustín García-Caballero, M. Parvaiz Farshori, J. Adolfo García-Sáinz and Kevin J. Catt
Molecular Pharmacology August 2005, 68 (2) 356-364; DOI: https://doi.org/10.1124/mol.104.010637
J. Alberto Olivares-Reyes
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Bukhtiar H. Shah
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Judith Hernández-Aranda
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Agustín García-Caballero
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M. Parvaiz Farshori
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J. Adolfo García-Sáinz
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Kevin J. Catt
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Abstract

In rat hepatic C9 cells, angiotensin II (Ang II)-induced activation of angiotensin type 1 (AT1) receptors (AT1-Rs) stimulates extracellular signal-regulated kinase (ERK) 1/2 phosphorylation via transactivation of the endogenous epidermal growth factor (EGF) receptor (EGF-R) by a protein kinase C (PKC) δ/Src/Pyk2-dependent pathway. This leads to phosphorylation of the EGF-R as well as its subsequent internalization. On the other hand, EGF-induced activation of the EGF-R in C9 cells was found to cause phosphorylation of the AT1-R. This was prevented by selective inhibition of the intrinsic tyrosine kinase activity of the EGF-R by AG1478 [4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline] and was reduced by inhibition of PKC and phosphoinositide 3-kinase. EGF-induced AT1-R phosphorylation was associated with a decrease in membrane-associated AT1-Rs and a reduced inositol phosphate response to Ang II. Agonist activation of endogenous AT1-Rs and EGF-Rs induced the formation of a multireceptor complex containing both the AT1-R and the transactivated EGF-R. The dependence of these responses on caveolin was indicated by the finding that cholesterol depletion of C9 cells abolished Ang II-induced inositol phosphate production, activation of Akt/PKB and ERK1/2, and AT1-R internalization. Confocal microscopy demonstrated that caveolin-1 was endogenously phosphorylated and was distributed on the plasma membrane in patches that undergo redistribution during Ang II stimulation. Agonist-induced phosphorylation and association of caveolin 1 with the AT1-R was observed, consistent with a scaffolding role of caveolin during transactivation of the EGF-R by Ang II. The EGF-induced AT1-R/caveolin association was abolished by AG1478, suggesting that activation of the EGF-R promotes the association of caveolin and the AT1-R.

  • Received December 21, 2004.
  • Accepted May 17, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 68 (2)
Molecular Pharmacology
Vol. 68, Issue 2
1 Aug 2005
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Research ArticleArticle

Agonist-Induced Interactions between Angiotensin AT1 and Epidermal Growth Factor Receptors

J. Alberto Olivares-Reyes, Bukhtiar H. Shah, Judith Hernández-Aranda, Agustín García-Caballero, M. Parvaiz Farshori, J. Adolfo García-Sáinz and Kevin J. Catt
Molecular Pharmacology August 1, 2005, 68 (2) 356-364; DOI: https://doi.org/10.1124/mol.104.010637

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Research ArticleArticle

Agonist-Induced Interactions between Angiotensin AT1 and Epidermal Growth Factor Receptors

J. Alberto Olivares-Reyes, Bukhtiar H. Shah, Judith Hernández-Aranda, Agustín García-Caballero, M. Parvaiz Farshori, J. Adolfo García-Sáinz and Kevin J. Catt
Molecular Pharmacology August 1, 2005, 68 (2) 356-364; DOI: https://doi.org/10.1124/mol.104.010637
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