title: Agonist-induced interactions between angiotensin AT1 and epidermal growth factor receptors.
abstract: In rat hepatic C9 cells, angiotensin II (Ang II)-induced activation of angiotensin type 1 (AT(1)) receptors (AT(1)-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) delta/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 AT(1)-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 AT(1)-R phosphorylation was associated with a decrease in membrane-associated AT(1)-Rs and a reduced inositol phosphate response to Ang II. Agonist activation of endogenous AT(1)-Rs and EGF-Rs induced the formation of a multireceptor complex containing both the AT(1)-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 AT(1)-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 AT(1)-R was observed, consistent with a scaffolding role of caveolin during transactivation of the EGF-R by Ang II. The EGF-induced AT(1)-R/caveolin association was abolished by AG1478, suggesting that activation of the EGF-R promotes the association of caveolin and the AT(1)-R.
authors.affiliation: Departamento de Bioquímica, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, A. P. 14-740 México, 07000 D. F., México. jolivare@cinvestav.mx
authors.forename: J Alberto
authors.initials: JA
authors.lastname: Olivares-Reyes
authors.forename: Bukhtiar H
authors.initials: BH
authors.lastname: Shah
authors.forename: Judith
authors.initials: J
authors.lastname: Hernández-Aranda
authors.forename: Agustín
authors.initials: A
authors.lastname: García-Caballero
authors.forename: M Parvaiz
authors.initials: MP
authors.lastname: Farshori
authors.forename: J Adolfo
authors.initials: JA
authors.lastname: García-Sáinz
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Catt
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism*; D006801:Humans; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D066246:ErbB Receptors