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Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma

Author

Listed:
  • Ling-Hui Zeng

    (Hangzhou City University School of Medicine)

  • Chao Tang

    (Zhejiang University School of Medicine
    the Children’s Hospital of Zhejiang University School of Medicine)

  • Minli Yao

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Qiangqiang He

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Meiyu Qv

    (Hangzhou City University School of Medicine
    Zhejiang University School of Medicine)

  • Qianlei Ren

    (Hangzhou City University School of Medicine)

  • Yana Xu

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Tingyu Shen

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Weizhong Gu

    (the Children’s Hospital of Zhejiang University School of Medicine)

  • Chengyun Xu

    (Hangzhou City University School of Medicine
    Zhejiang University School of Medicine
    the Children’s Hospital of Zhejiang University School of Medicine)

  • Chaochun Zou

    (the Children’s Hospital of Zhejiang University School of Medicine)

  • Xing Ji

    (Hangzhou City University School of Medicine
    Zhejiang University School of Medicine)

  • Ximei Wu

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Jirong Wang

    (Zhejiang Hospital)

Abstract

Aberrant activation of sonic hedgehog (SHH) signaling and its effector transcriptional factor GLI1 are essential for oncogenesis of SHH-dependent medulloblastoma (MBSHH) and basal cell carcinoma (BCC). Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1’s proteasomal degradation and negates the transcription of SHH signaling. As a result, Gli1S941E loss-of-function knock-in significantly reduces the incidence and severity of smoothened-M2 transgene-induced spontaneous MBSHH, whereas Gli1S941A gain-of-function knock-in phenocopies Gli1 transgene in causing BCC-like proliferation in skin. Correspondingly, phospho-Ser937-GLI1, a destabilized form of GLI1, positively correlates to the overall survival rate of children with MBSHH. Together, these findings indicate that SHH-induced p38α inactivation and subsequent GLI1 dephosphorylation and stabilization in controlling SHH signaling and may provide avenues for future interventions of MBSHH and BCC.

Suggested Citation

  • Ling-Hui Zeng & Chao Tang & Minli Yao & Qiangqiang He & Meiyu Qv & Qianlei Ren & Yana Xu & Tingyu Shen & Weizhong Gu & Chengyun Xu & Chaochun Zou & Xing Ji & Ximei Wu & Jirong Wang, 2024. "Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45315-x
    DOI: 10.1038/s41467-024-45315-x
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    References listed on IDEAS

    as
    1. Patryk Skowron & Hamza Farooq & Florence M. G. Cavalli & A. Sorana Morrissy & Michelle Ly & Liam D. Hendrikse & Evan Y. Wang & Haig Djambazian & Helen Zhu & Karen L. Mungall & Quang M. Trinh & Tina Zh, 2021. "The transcriptional landscape of Shh medulloblastoma," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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