Stress Response Kinase MK2 Induces Non-canonical Activation of EphA2 in EML4-ALK Lung Cancer Cells

Fang Zhang; Yue Zhou; Naru Hamada; Akihiro Tanaka; Satoru Yokoyama; Seiji Yano; Kunio Matsumoto; Hiroyuki Mano; Hiroaki Sakurai

doi:10.1248/bpb.b24-00747

Regular Article

Stress Response Kinase MK2 Induces Non-canonical Activation of EphA2 in EML4-ALK Lung Cancer Cells

Fang Zhang ^†, Yue Zhou ^†, Naru Hamada, Akihiro Tanaka, Satoru Yokoyama, Seiji Yano, Kunio Matsumoto, Hiroyuki Mano, Hiroaki Sakurai

Author information

Fang Zhang ^†
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930–0194, Japan
Yue Zhou ^†
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930–0194, Japan
Naru Hamada
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930–0194, Japan
Akihiro Tanaka
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930–0194, Japan
Satoru Yokoyama
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930–0194, Japan
Seiji Yano
Department of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Science, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920–0934, Japan
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920–0934, Japan
WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920–1164, Japan
Kunio Matsumoto
WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920–1164, Japan
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920–1192, Japan
Hiroyuki Mano
Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104–0045, Japan
Hiroaki Sakurai Corresponding author
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930–0194, Japan
Author contributions

†These authors contributed equally: Fang Zhang, Yue Zhou

Keywords: ephrin type-A receptor 2 (EphA2), mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), p90 ribosomal S6 kinase (RSK)

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Supplementary material

2025 Volume 48 Issue 2 Pages 172-176

DOI https://doi.org/10.1248/bpb.b24-00747

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Abstract

The non-canonical phosphorylation of the receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) at Ser-897 plays crucial roles in tumor progression in a tyrosine kinase-independent manner. This phosphorylation is catalyzed by p90 ribosomal S6 kinase (RSK), a kinase downstream of extracellular signal-regulated kinase (ERK). We recently reported that stress-responsive kinase mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), instead of ERK, regulates RSK under cellular stress conditions; however, the function of MK2 in ERK-activated cells is still unknown. We herein clarified that MK2 regulates the RSK-EphA2 axis in ERK-activated echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) lung cancer cells. In addition, an MK2 inhibitor blocked enhancements in cell motility induced by the constitutively activated RSK-EphA2 axis. The present results reveal the importance of MK2 in the ERK-activated non-canonical activation of EphA2.

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