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MEK1-RSK2 contributes to Hedgehog signaling by stabilizing GLI2 transcription factor and inhibiting ubiquitination

Z Liu1, T Li2, M I Reinhold3

  • 11] Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA [2] Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Oncogene
|December 5, 2012
PubMed

Insights

The MEK-RSK pathway stabilizes GLI2 protein by inhibiting GSK-3β-mediated degradation, offering a new therapeutic target for multiple myeloma by enhancing GLI2 levels.

Area of Science:

  • Molecular Biology
  • Oncology
  • Signal Transduction

Background:

  • GLI2 is a key transcription factor in Hedgehog signaling, crucial for tumorigenesis in various human cancers.
  • Mechanisms regulating GLI2 protein expression and stability remain incompletely understood, hindering targeted therapeutic development.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling GLI2 protein stability.
  • To investigate the role of the MEK-ERK-RSK signaling pathway in GLI2 regulation.
  • To explore the therapeutic potential of targeting the MEK-RSK pathway in multiple myeloma.

Main Methods:

  • Investigated GLI2 modulation by MEK1 at mRNA and protein levels.
  • Assessed the impact of MEK1 and RSK2 on GLI2 half-life, nuclear translocation, and ubiquitination.
  • Utilized GLI2 mutants lacking GSK-3β phosphorylation sites to determine MEK-RSK's mechanism of action.
  • Compared GLI2 protein levels in multiple myeloma cells versus normal B cells.
  • Evaluated the synergistic effect of RSK and GLI inhibitors on multiple myeloma cell apoptosis.

Main Results:

  • Mitogen-activated protein kinase kinase 1 (MEK1) stabilizes GLI2 protein by prolonging its half-life and enhancing nuclear translocation.
  • RSK2, downstream of MEK-ERK, mimics MEK1's effect on GLI2 stabilization.
  • MEK-RSK pathway stabilizes GLI2 by inhibiting glycogen synthase kinase-3 beta (GSK-3β)-dependent phosphorylation and subsequent ubiquitination.
  • Activated MEK-RSK signaling correlates with elevated GLI2 protein levels in multiple myeloma cells.
  • Combined inhibition of RSK and GLI significantly enhances apoptosis in multiple myeloma cells.

Conclusions:

  • The MEK-RSK signaling cascade positively regulates GLI2 protein stability by inhibiting its degradation.
  • This pathway functions by suppressing GSK-3β-mediated phosphorylation and ubiquitination of GLI2.
  • Targeting the MEK-RSK pathway presents a promising therapeutic strategy for multiple myeloma, potentially by sensitizing cells to GLI inhibitors.

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