Related Experiment Video

Updated: Sep 13, 2025

Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
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Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle

Published on: March 5, 2019

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Non-canonical Activation of RSK1 Induces EphA2-Mediated Cell Migration under Cellular Stress Conditions

Yue Zhou1, Fang Zhang1, Akihiro Tanaka1

  • 1Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan.

Biological & Pharmaceutical Bulletin
|July 28, 2025
PubMed

Insights

A novel pathway activates p90 ribosomal S6 kinase 1 (RSK1) through 3-phosphoinositide-dependent kinase 1 (PDK1) and mitogen-activated protein kinase-activated protein kinase 2 (MK2). This PDK1-MK2-RSK1-EphA2 axis drives glioblastoma cell migration, offering new insights into cancer malignancy.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • p90 ribosomal S6 kinase 1 (RSK1) is crucial for cell growth and migration.
  • RSK1 phosphorylation of ephrin receptor A2 (EphA2) at Ser-897 promotes cancer cell migration.
  • RSK1 activation is regulated by extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase-activated protein kinase 2 (MK2), with the MK2 pathway less understood.

Purpose of the Study:

  • To elucidate the mechanism of RSK1 activation by MK2.
  • To investigate the role of the PDK1-MK2-RSK1-EphA2 signaling axis in glioblastoma.
  • To understand the contribution of this pathway to temozolomide-induced cell migration.

Main Methods:

  • Investigated RSK1 phosphorylation sites, specifically Ser-380 and Ser-221.
  • Utilized biochemical assays to determine kinase dependencies (PDK1, MK2, ERK).
  • Examined the functional impact on glioblastoma cell migration in response to temozolomide.

Main Results:

  • MK2-mediated RSK1 phosphorylation at Ser-380 requires basal phosphorylation at Ser-221.
  • Ser-221 basal phosphorylation is catalyzed by 3-phosphoinositide-dependent kinase 1 (PDK1) and is independent of ERK.
  • The PDK1-MK2-RSK1-EphA2 pathway significantly promotes glioblastoma cell migration induced by temozolomide.

Conclusions:

  • Revealed a novel, PDK1-dependent activation mechanism for RSK1 via MK2.
  • Identified a new signaling axis (PDK1-MK2-RSK1-EphA2) crucial for glioblastoma cell migration.
  • This pathway represents a potential therapeutic target for enhancing chemotherapy efficacy in glioblastoma.
Keywords:
cell migrationephrin receptor A2mitogen-activated protein kinase-activated protein kinase 2p90 ribosomal S6 kinase 1

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