The β2-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor
The β2-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor
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DOI：
10.1074/jbc.275.13.9572
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发表时间：
2000-03-31
影响因子：
4.8
通讯作者：
Luttrell, LM
中科院分区：
文献类型：
--
作者：
Maudsley, S;Pierce, KL;Luttrell, LM
许多 G 蛋白偶联受体 (GPCR) 通过刺激酪氨酸激酶信号级联来激活 MAP 激酶。在一些系统中，GPCR 通过诱导受体酪氨酸激酶 (RTK) 的“反式激活”来刺激酪氨酸磷酸化。GPCR 诱导的 RTK 反式激活的机制尚未明确定义。在此，我们报道 GPCR 激活在 RTK 功能的许多方面模拟了生长因子介导的表皮生长因子受体 (EGFR) 刺激。 β(2)-肾上腺素能受体 (β(2)AR) 刺激 COS-7 细胞可诱导 EGFR 二聚化、酪氨酸自磷酸化和 EGFR 内化。与 EGFR 反式激活同时发生，异丙肾上腺素暴露诱导包含 β(2)AR 和“反式激活”EGFR 的多受体复合物的形成。 beta(2)AR 介导的 EGFR 磷酸化和随后的细胞外信号调节激酶 (ERK) 1/2 的 beta(2)AR 刺激对 EGFR 和 Src 激酶的选择性抑制剂敏感，表明这两种激酶都是 EGFR 反式激活所必需的。 ERK1/2 的 beta(2)AR 依赖性信号传导，就像直接 EGF 刺激 ERK1/2 活性一样，对网格蛋白介导的内吞作用抑制剂敏感，这表明 EGF 激活和 GPCR 反式激活 EGFR 的下游信号传导需要复合物与细胞内吞机制的有效结合，因此，RTK 反式激活是一个涉及不同类别受体关联以及反式激活 RTK 与细胞相互作用的过程。内吞机器。
Many G protein-coupled receptors (GPCRs) activate MAP kinases by stimulating tyrosine kinase signaling cascades. In some systems, GPCRs stimulate tyrosine phosphorylation by inducing the "transactivation" of a receptor tyrosine kinase (RTK), The mechanisms underlying GPCR-induced RTK transactivation have not been clearly defined. Here we report that GPCR activation mimics growth factor-mediated stimulation of the epidermal growth factor receptor (EGFR) with respect to many facets of RTK function. beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR dimerization, tyrosine autophosphorylation, and EGFR internalization. Coincident with EGFR transactivation, isoproterenol exposure induces the formation of a multireceptor complex containing both the beta(2)AR and the "transactivated" EGFR. beta(2)AR-mediated EGFR phosphorylation and subsequent beta(2)AR stimulation of extracellular signal-regulated kinase (ERK) 1/2 are sensitive to selective inhibitors of both EGFR and Src kinases, indicating that both kinases are required for EGFR transactivation. beta(2)AR-dependent signaling to ERK1/2, like direct EGF stimulation of ERK1/2 activity, is sensitive to inhibitors of clathrin-mediated endocytosis, suggesting that signaling downstream of both the EGF-activated and the GPCR-transactivated EGFRs requires a productive engagement of the complex with the cellular endocytic machinery, Thus, RTK transactivation is revealed to be a process involving both association of receptors of distinct classes and the interaction of the transactivated RTK with the cells endocytic machinery.