ERK3/MAPK6 controls IL-8 production and chemotaxis
ERK3/MAPK6 controls IL-8 production and chemotaxis
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DOI：
10.7554/elife.52511
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发表时间：
2020-04-21
期刊：
影响因子：
7.7
通讯作者：
Rajalingam, Krishnaraj
中科院分区：
文献类型：
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作者：
Bogucka, Katarzyna;Pompaiah, Malvika;Rajalingam, Krishnaraj
ERK3是非典型丝裂原活化蛋白激酶（MAPKs）中普遍表达的成员，其半衰期短的生理意义尚不清楚。通过使用胃肠道三维类器官，我们发现ERK3蛋白水平在上皮分化过程中稳步下降。人胃上皮三维生长不需要ERK3。然而，ERK3在致瘤细胞中是稳定和激活的，但随着时间的推移，在原代细胞中，ERK3在脂多糖（LPS）的作用下会恶化。ERK3对于包括白细胞介素-8 （IL-8）在内的几种细胞因子的产生是必需的，在正常细胞和致瘤细胞中都是如此。特别是，ERK3通过其相互作用和调节c-Jun蛋白对AP-1信号传导至关重要。erk3缺陷细胞的分泌组在体外和体内对中性粒细胞和单核细胞的趋化性有缺陷。此外，敲低ERK3可降低浸润性乳腺癌细胞的转移潜能。我们揭示了erk3介导的IL-8和上皮分泌组的趋化调节。
ERK3 is a ubiquitously expressed member of the atypical mitogen activated protein kinases (MAPKs) and the physiological significance of its short half-life remains unclear. By employing gastrointestinal 3D organoids, we detect that ERK3 protein levels steadily decrease during epithelial differentiation. ERK3 is not required for 3D growth of human gastric epithelium. However, ERK3 is stabilized and activated in tumorigenic cells, but deteriorates over time in primary cells in response to lipopolysaccharide (LPS). ERK3 is necessary for production of several cellular factors including interleukin-8 (IL-8), in both, normal and tumorigenic cells. Particularly, ERK3 is critical for AP-1 signaling through its interaction and regulation of c-Jun protein. The secretome of ERK3-deficient cells is defective in chemotaxis of neutrophils and monocytes both in vitro and in vivo. Further, knockdown of ERK3 reduces metastatic potential of invasive breast cancer cells. We unveil an ERK3-mediated regulation of IL-8 and epithelial secretome for chemotaxis.