β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation
β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation
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DOI：
10.1073/pnas.0804745105
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发表时间：
2008-09-23
影响因子：
11.1
通讯作者：
Rockman, Howard A.
中科院分区：
文献类型：
--
作者：
Kim, Il-Man;Tilley, Douglas G.;Rockman, Howard A.
最近的证据表明，激动剂与其同源受体的结合不仅启动经典的G蛋白介导的信号传导，还启动β -抑制蛋白依赖的信号传导。一种β -抑制素介导的途径使用β(1)-肾上腺素能受体（β (1)AR）来反激活EGFR。为了确定不激活G蛋白信号的β -肾上腺素能配体（即β受体阻滞剂）是否可以稳定信号构象中的β (1)AR，我们筛选了20种β受体阻滞剂，以观察它们刺激β -抑制素介导的EGFR转激活的能力。本研究表明，只有阿普萘洛尔（Alp）和卡维地洛尔（Car）可诱导β (1) ar介导的EGFR转激活和下游ERK激活。通过使用缺乏G蛋白偶联受体激酶磷酸化位点的β (1)AR突变体和针对β -抑制蛋白的siRNA，我们发现Alp和car刺激的EGFR反式激活需要β (1)AR在一致的G蛋白偶联受体激酶位点磷酸化和β -抑制蛋白募集到配体占据的受体。此外，Src和EGFR的药理抑制阻断了Alp和car刺激的EGFR转激活。我们的研究结果表明，Alp和Car是配体，不仅作为经典受体拮抗剂，而且还可以以不依赖G蛋白、依赖β -抑制蛋白的方式刺激信号通路。
Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also beta-arrestin-dependent signaling. One such beta-arrestin-mediated pathway uses the beta(1)-adrenergic receptor (beta(1)AR) to transactivate the EGFR. To determine whether beta-adrenergic ligands that do not activate G protein signaling (i.e., beta-blockers) can stabilize the beta(1)AR in a signaling conformation, we screened 20 beta-blockers for their ability to stimulate beta-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce beta(1)AR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the beta(1)AR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against beta-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires beta(1)AR phosphorylation at consensus G protein-coupled receptor kinase sites and beta-arrestin recruitment to the ligand-occupied receptor. Moreover, pharmacological inhibition of Src and EGFR blocked Alp- and Car-stimulated EGFR transactivation. Our findings demonstrate that Alp and Car are ligands that not only act as classical receptor antagonists, but can also stimulate signaling pathways in a G protein-independent, beta-arrestin-dependent fashion.