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

  • Biol Pharm Bull. 2025;48(2):172-176. doi: 10.1248/bpb.b24-00747.
Fang Zhang  1 ,  Yue Zhou  1 ,  Naru Hamada  1 ,  Akihiro Tanaka  1 ,  Satoru Yokoyama  1 ,  Seiji Yano  2  3  4 ,  Kunio Matsumoto  4  5 ,  Hiroyuki Mano  6 ,  Hiroaki Sakurai  1
Affiliations
  • 1. Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan.
  • 2. Department of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Science, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
  • 3. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
  • 4. WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1164, Japan.
  • 5. Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
  • 6. Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
PMID: 40024717 DOI: 10.1248/bpb.b24-00747
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.

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