Division of Tumor Cell Biology and Bioimaging, Cancer Research Institute of Kanazawa University, Ishikawa 920-1192, Japan.
Department of Oncologic Pathology, School of Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan.
Int J Mol Sci. 2019 Feb 5;20(3):679. doi: 10.3390/ijms20030679.
Extracellular signal-regulated kinase (ERK) is a major downstream factor of the EGFR-RAS-RAF signalling pathway, and thus the role of ERK in cell growth has been widely examined. The development of biosensors based on fluorescent proteins has enabled us to measure ERK activities in living cells, both after growth factor stimulation and in its absence. Long-term imaging unexpectedly revealed the oscillative activation of ERK in an epithelial sheet or a cyst in vitro. Studies using transgenic mice expressing the ERK biosensor have revealed inhomogeneous ERK activities among various cell species. In vivo Förster (or fluorescence) resonance energy transfer (FRET) imaging shed light on a novel role of ERK in cell migration. Neutrophils and epithelial cells in various organs such as intestine, skin, lung and bladder showed spatio-temporally different cell dynamics and ERK activities. Experiments using inhibitors confirmed that ERK activities are required for various pathological responses, including epithelial repair after injuries, inflammation, and niche formation of cancer metastasis. In conclusion, biosensors for ERK will be powerful and valuable tools to investigate the roles of ERK in situ.
细胞外信号调节激酶（ERK）是 EGFR-RAS-RAF 信号通路的主要下游因子，因此 ERK 在细胞生长中的作用已被广泛研究。基于荧光蛋白的生物传感器的发展使我们能够测量生长因子刺激前后以及无生长因子刺激时活细胞中的 ERK 活性。长期成像出人意料地揭示了 ERK 在体外上皮片或囊泡中的振荡激活。使用表达 ERK 生物传感器的转基因小鼠进行的研究表明，各种细胞类型之间的 ERK 活性存在不均匀性。体内Förster（或荧光）共振能量转移（FRET）成像揭示了 ERK 在细胞迁移中的新作用。来自肠道、皮肤、肺和膀胱等各种器官的中性粒细胞和上皮细胞显示出时空上不同的细胞动力学和 ERK 活性。使用抑制剂进行的实验证实，ERK 活性是各种病理反应所必需的，包括损伤后上皮修复、炎症和癌症转移龛形成。总之，ERK 的生物传感器将是研究 ERK 原位作用的强大而有价值的工具。
