Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner
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Protein & Cell
RESEARCH ARTICLE Extracellular signal regulated kinase 5 promotes cell migration, invasion and lung metastasis in a FAK-dependent manner Weiwei Jiang1, Fangfang Cai1, Huangru Xu1, Yanyan Lu1, Jia Chen1, Jia Liu1, Nini Cao1, Xiangyu Zhang1, Xiao Chen1, Qilai Huang1, Hongqin Zhuang1&, Zi-Chun Hua1,2& The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210023, China 2 Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou 213164, China & Correspondence: [email protected] (H. Zhuang), [email protected] (Z.-C. Hua) Received December 3, 2019 Accepted February 9, 2020
ABSTRACT This study was designed to evaluate ERK5 expression in lung cancer and malignant melanoma progression and to ascertain the involvement of ERK5 signaling in lung cancer and melanoma. We show that ERK5 expression is abundant in human lung cancer samples, and elevated ERK5 expression in lung cancer was linked to the acquisition of increased metastatic and invasive potential. Importantly, we observed a significant correlation between ERK5 activity and FAK expression and its phosphorylation at the Ser910 site. Mechanistically, ERK5 increased the expression of the transcription factor USF1, which could transcriptionally upregulate FAK expression, resulting in FAK signaling activation to promote cell migration. We also provided evidence that the phosphorylation of FAK at Ser910 was due to ERK5 but not ERK1/2, and we then suggested a role for Ser910 in the control of cell motility. In addition, ERK5 had targets in addition to FAK that regulate epithelial-to-mesenchymal transition and cell motility in cancer cells. Taken together, our findings uncover a cancer metastasis-promoting role for ERK5 and provide the rationale for targeting ERK5 as a potential therapeutic approach.
Weiwei Jiang and Fangfang Cai have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13238-020-00701-1) contains supplementary material, which is available to authorized users.
© The Author(s) 2020
KEYWORDS ERK5, lung cancer, melanoma, metastasis, FAK, USF1, EMT
INTRODUCTION Lung cancer remains the leading cause of cancer-related death worldwide, among which non-small cell lung cancer (NSCLC) accounts for approximately 85% of all types of lung cancer (Siegel et al., 2018). Over the past decade, despite the development of new therapeutic options for cancer treatment, the prognosis of patients with lung cancer still remains unsatisfactory due to the lack of understanding of the molecular mechanisms of intrapulmonary and extrapulmonary metastasis, especially for invasive and metastatic NSCLC. Therefore, exploring the mechanisms underlying the metastasis and invasion of lung cancer is important for establishing new therapeutic targets to improve lung cancer treatment. Metastasis is a complex process by which tumor cells disseminate from their primary site and form secondary
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