RT Journal Article SR Electronic T1 Agonist-Induced Interactions between Angiotensin AT1 and Epidermal Growth Factor Receptors JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 356 OP 364 DO 10.1124/mol.104.010637 VO 68 IS 2 A1 J. Alberto Olivares-Reyes A1 Bukhtiar H. Shah A1 Judith Hernández-Aranda A1 Agustín García-Caballero A1 M. Parvaiz Farshori A1 J. Adolfo García-Sáinz A1 Kevin J. Catt YR 2005 UL http://molpharm.aspetjournals.org/content/68/2/356.abstract AB 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.