Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
Nature. 2022 Nov;611(7934):173-179. doi: 10.1038/s41586-022-05343-3. Epub 2022 Oct 26.
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 survival. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood. Here we investigated how spatially organized β-adrenergic receptor (βAR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors, we show that βAR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gα and requires ligand-stimulated βAR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gα, RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal βAR and Gα 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.
G 蛋白偶联受体（GPCRs）是信号转导受体中最大的家族，也是重要的药物靶点，已知其可激活细胞外信号调节激酶（ERK）——细胞增殖和存活的主要调节剂。然而，GPCR 介导的 ERK 激活的确切机制尚不清楚。在这里，我们研究了空间组织的β-肾上腺素能受体（βAR）信号如何控制 ERK。使用亚细胞靶向 ERK 活性生物传感器，我们表明βAR 信号在内涵体上诱导 ERK 活性，但不在质膜上。这种 ERK 活性依赖于活跃的、定位于内涵体的 Gα，并且需要配体刺激的βAR 内吞作用。我们进一步鉴定了一个包含 Gα、RAF 和丝裂原活化蛋白激酶激酶的内涵体局部非典型信号轴，导致内涵体 ERK 活性向核内传递。选择性抑制内涵体βAR 和 Gα 信号会削弱核 ERK 活性、MYC 基因表达和细胞增殖。这些结果揭示了通过 GPCR 信号对 ERK 进行空间调节的非典型机制，并鉴定了一个具有重要功能的内涵体信号轴。
