美国加州大学圣迭戈分校Jin Zhang研究组揭示ERK在内体上的非经典β-肾上腺素能激活。相关论文于2022年10月26日在线发表在《自然》杂志上。

研究人员阐明了空间组织的β₂-肾上腺素受体（β₂AR）信号如何控制细胞外信号调节激酶（ERK）。使用亚细胞靶向ERK活性生物传感器，研究人员表明，β₂AR信号诱导ERK在内体而非质膜上的活性。这个ERK活性池依赖于活跃的内体定位Gα_s，并需要配体刺激的β₂AR内吞作用。研究人员进一步确定了由Gα_s、RAF和丝裂原活化蛋白激酶组成的内体定位的非经典信号轴，其导致内体ERK活性传播到细胞核。选择性地抑制内体β₂AR和Gα_s信号，使核ERK活性、MYC基因表达和细胞增殖减弱。

这些结果揭示了通过G-蛋白偶联受体（GPCR）信号对ERK进行空间调控的非经典机制，并确定了一个功能上重要的内体信号轴。

据介绍，GPCR是最大的信号受体家族，也是重要的药物靶点，已知可激活ERK——细胞增殖和生存的主要调节因子。然而，人们对GPCR介导的ERK激活的确切机制并不清楚。

附：英文原文

Title: Non-canonical β-adrenergic activation of ERK at endosomes

Author: Kwon, Yonghoon, Mehta, Sohum, Clark, Mary, Walters, Geneva, Zhong, Yanghao, Lee, Ha Neul, Sunahara, Roger K., Zhang, Jin

Issue&Volume: 2022-10-26

Abstract: G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)—a master regulator of cell proliferation and survival1. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood2,3,4. Here we investigated how spatially organized β2-adrenergic receptor (β2AR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors5, we show that β2AR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gαs and requires ligand-stimulated β2AR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gαs, RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal β2AR and Gαs signalling blunted nuclear ERK activity, MYC gene expression and cell proliferation. These results reveal a non-canonical mechanism for the spatial regulation of ERK through GPCR signalling and identify a functionally important endosomal signalling axis.

DOI: 10.1038/s41586-022-05343-3

Source: https://www.nature.com/articles/s41586-022-05343-3