Cellular stress induces non-canonical activation of the receptor tyrosine kinase EphA2 through the p38-MK2-RSK signaling pathway

Cellular stress induces non-canonical activation of the receptor tyrosine kinase EphA2 through the p38-MK2-RSK signaling pathway

The receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) is overexpressed in malignant tumors. We previously reported that non-canonical EphA2 phosphorylation at Ser-897 was catalyzed by p90 ribosomal S6 kinase (RSK) via the MEK-ERK pathway in ligand- and tyrosine kinase-independent manners. No...

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Bibliographic Details
Published in:The Journal of biological chemistry Vol. 299; no. 5; p. 104699
Main Authors: Zhou, Yue, Oki, Ryota, Tanaka, Akihiro, Song, Leixin, Takashima, Atsushi, Hamada, Naru, Yokoyama, Satoru, Yano, Seiji, Sakurai, Hiroaki
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-05-2023
American Society for Biochemistry and Molecular Biology
Subjects:
cellular stress
EphA2
Glioblastoma
Humans
MAP Kinase Signaling System - physiology
migration
MK2
p38
Phosphorylation
Receptor Protein-Tyrosine Kinases - metabolism
Receptor, EphA2 - metabolism
Ribosomal Protein S6 Kinases, 90-kDa - genetics
Ribosomal Protein S6 Kinases, 90-kDa - metabolism
RSK
Signal Transduction
Tumor Microenvironment
TMZ
NTK
TPA
EGF
RSK
CDK
EMT
EphA2
cellular stress
MMP
CDDP
MEK
p38
MK2
CTKD
HSP27
migration
CTK
NTKD
ERK
PDK1
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Summary:The receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) is overexpressed in malignant tumors. We previously reported that non-canonical EphA2 phosphorylation at Ser-897 was catalyzed by p90 ribosomal S6 kinase (RSK) via the MEK-ERK pathway in ligand- and tyrosine kinase-independent manners. Non-canonical EphA2 activation plays a key role in tumor progression; however, its activation mechanism remains unclear. In the present study, we focused on cellular stress signaling as a novel inducer of non-canonical EphA2 activation. p38, instead of ERK in the case of epidermal growth factor signaling, activated RSK-EphA2 under cellular stress conditions, including anisomycin, cisplatin, and high osmotic stress. Notably, p38 activated the RSK-EphA2 axis via downstream MAPK-activated protein kinase 2 (MK2). Furthermore, MK2 directly phosphorylated both RSK1 Ser-380 and RSK2 Ser-386, critical residues for the activation of their N-terminal kinases, which is consistent with the result showing that the C-terminal kinase domain of RSK1 was dispensable for MK2-mediated EphA2 phosphorylation. Moreover, the p38-MK2-RSK-EphA2 axis promoted glioblastoma cell migration induced by temozolomide, a chemotherapeutic agent for the treatment of glioblastoma patients. Collectively, the present results reveal a novel molecular mechanism for non-canonical EphA2 activation under stress conditions in the tumor microenvironment.
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content type line 23
ISSN:0021-9258
1083-351X
DOI:10.1016/j.jbc.2023.104699