Agonist-induced interactions between angiotensin AT1 and epidermal growth factor receptors
Agonist-induced interactions between angiotensin AT1 and epidermal growth factor receptors
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DOI：
10.1124/mol.104.010637
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发表时间：
2005-08-01
影响因子：
3.6
通讯作者：
Catt, KJ
中科院分区：
文献类型：
--
作者：
Olivares-Reyes, JA;Shah, BH;Catt, KJ
在大鼠肝C9细胞中，血管紧张素II（Ang II）诱导的血管紧张素1型（AT（1））受体（AT（1）-Rs）激活通过蛋白激酶C（PKC）delta/Src/Pyk 2依赖性途径反式激活内源性表皮生长因子（EGF）受体（EGF-R），刺激细胞外信号调节激酶（ERK）1/2磷酸化。这导致EGF-R的磷酸化及其随后的内化。另一方面，发现EGF诱导的C9细胞中EGF-R的活化导致AT（1）-R的磷酸化。这通过AG 1478 [4-（3 '-chloroanilino）-6，7-dimethoxyquinazoline]选择性抑制EGF-R的固有酪氨酸激酶活性来防止，并通过抑制PKC和磷酸肌醇3-激酶来降低。EGF诱导的AT（1）-R磷酸化与膜相关AT（1）-R的减少和对Ang II的磷酸肌醇反应降低有关。内源性AT（1）-R和EGF-R的激动剂激活诱导了一种含有AT（1）-R和反式激活的EGF-R的多受体复合物的形成。这些反应依赖于小窝蛋白，这一发现表明，C9细胞的胆固醇消耗消除了Ang II诱导的磷酸肌醇的产生，Akt/PKB和ERK 1/2的激活，以及AT（1）-R的内化。共聚焦显微镜表明，小窝蛋白-1内源性磷酸化，并分布在质膜上的补丁，在血管紧张素II刺激过程中进行重新分配。激动剂诱导的磷酸化和小窝蛋白1与AT（1）-R的关联被观察到，与小窝蛋白在Ang II反式激活EGF-R过程中的支架作用一致。EGF诱导的AT（1）-R/小窝蛋白结合被AG 1478消除，表明EGF-R的激活促进了小窝蛋白和AT（1）-R的结合。
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-dimethoxyquinazoline] 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.