ERK3/MAPK6 controls IL-8 production and chemotaxis

• Published in: eLife Vol. 9
• Main Authors: Bogucka, Katarzyna, Pompaiah, Malvika, Marini, Federico, Binder, Harald, Harms, Gregory, Kaulich, Manuel, Klein, Matthias, Michel, Christian, Radsak, Markus P, Rosigkeit, Sebastian, Grimminger, Peter, Schild, Hansjörg, Rajalingam, Krishnaraj
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 21-04-2020; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Animals; Breast cancer; c-Jun protein; Cancer cells; Cancer metastasis; Cell Biology; Cell Line; Chemotaxis; Chemotaxis, Leukocyte - physiology; Epithelium; ERK3; Gene expression; Gene Expression Regulation - physiology; Heterografts; Humans; Interleukin 8; Interleukin-8 - metabolism; Interleukins; Invasiveness; Jun protein; Keratin; Kinases; Leukocytes (neutrophilic); Lipopolysaccharides; MAPK; Metastases; Metastasis; Mice; Mitogen-Activated Protein Kinase 6 - metabolism; Mitogens; Monocytes; Morphogenesis; Organoids; Pharmaceutical industry; Phosphorylation; Physiological aspects; Physiology; Protein kinases; Proteins; Scientific equipment industry; Secretome; signal transduction; Time; Transcription factors; United States; mouse; cell biology; ERK3; gastrointestinal organoids; metastasis; signal transduction; IL-8; MAPK; secretome; human; chemotaxis
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.52511

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.