Transactivation of the EGF receptor as a novel desensitization mechanism for G protein-coupled receptors, illustrated by dopamine D2-like and β2 adrenergic receptors.

IF 9.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cellular & Molecular Biology Letters Pub Date : 2024-10-28 DOI:10.1186/s11658-024-00652-z
Dooti Kundu, Xiao Min, Shujie Wang, Lulu Peng, Xinru Tian, Mengling Wang, Kyeong-Man Kim
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Abstract

Transactivation of epidermal growth factor receptors (EGFR) provides intricate control over multiple regulatory cellular processes that merge the diversity of G protein-coupled receptors (GPCRs) with the robust signaling capacities of receptor tyrosine kinases. Contrary to the typical assertions, our findings demonstrate that EGFR transactivation contributes to the desensitization of GPCRs. Repeated agonist stimulation of certain GPCRs enhanced EGFR transactivation, triggering a series of cellular events associated with GPCR desensitization. This effect was observed in receptors undergoing desensitization (D3R, K149C-D2R, β2AR) but not in those resistant to desensitization (D2R, C147K-D3R, D4R, β2AR mutants lacking GRK2 or GRK6 phosphorylation sites). The EGFR inhibitor AG1478 prevented both desensitization and the associated cellular events. Similarly, these cellular events were also observed when cells were treated with EGF, but only in GPCRs that undergo desensitization. These findings suggest that EGFR transactivation diversifies pathways involved in ERK activation through the EGFR signaling system and also mediates GPCR desensitization. Alongside the widely accepted steric hindrance model, these findings offer new insights into understanding the mechanisms of GPCR desensitization, which occurs through complex cellular processes.

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以多巴胺 D2 样受体和 β2 肾上腺素能受体为例,说明 EGF 受体的反式激活是 G 蛋白偶联受体的一种新型脱敏机制。
表皮生长因子受体(表皮生长因子受体)的反式激活提供了对多种细胞调控过程的复杂控制,这些过程融合了 G 蛋白偶联受体(GPCR)的多样性和受体酪氨酸激酶的强大信号能力。与通常的说法相反,我们的研究结果表明,表皮生长因子受体的反式激活有助于 GPCR 的脱敏。某些 GPCR 受激动剂的反复刺激增强了表皮生长因子受体的转录活化,引发了一系列与 GPCR 脱敏相关的细胞事件。这种效应可在正在脱敏的受体(D3R、K149C-D2R、β2AR)中观察到,但在对脱敏有抵抗力的受体(D2R、C147K-D3R、D4R、缺乏 GRK2 或 GRK6 磷酸化位点的 β2AR 突变体)中却观察不到。表皮生长因子受体抑制剂 AG1478 阻止了脱敏和相关的细胞事件。同样,用表皮生长因子受体处理细胞时也观察到了这些细胞事件,但只是在发生脱敏的 GPCR 中。这些研究结果表明,表皮生长因子受体的反式激活通过表皮生长因子受体信号系统使参与ERK激活的途径多样化,同时也介导了GPCR脱敏。除了广为接受的立体阻碍模型外,这些发现还为了解 GPCR 脱敏机制提供了新的见解,而 GPCR 脱敏是通过复杂的细胞过程发生的。
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来源期刊
Cellular & Molecular Biology Letters
Cellular & Molecular Biology Letters 生物-生化与分子生物学
CiteScore
11.60
自引率
13.30%
发文量
101
审稿时长
3 months
期刊介绍: Cellular & Molecular Biology Letters is an international journal dedicated to the dissemination of fundamental knowledge in all areas of cellular and molecular biology, cancer cell biology, and certain aspects of biochemistry, biophysics and biotechnology.
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