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

  • Nat Commun. 2024 Feb 2;15(1):987. doi: 10.1038/s41467-024-45315-x.
Ling-Hui Zeng  #  1 ,  Chao Tang  #  2  3 ,  Minli Yao  #  2  4 ,  Qiangqiang He  2  4 ,  Meiyu Qv  5  2 ,  Qianlei Ren  5 ,  Yana Xu  2  4 ,  Tingyu Shen  2  4 ,  Weizhong Gu  3 ,  Chengyun Xu  5  2  3 ,  Chaochun Zou  3 ,  Xing Ji  5  2 ,  Ximei Wu  6  7 ,  Jirong Wang  8
Affiliations
  • 1. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang, Province, Hangzhou City University School of Medicine, Hangzhou, 310015, China. [email protected].
  • 2. Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 3. National Clinical Research Center for Child Health, the Children's Hospital of Zhejiang University School of Medicine, Hangzhou, 310053, China.
  • 4. Department of Orthopaedics, the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 5. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang, Province, Hangzhou City University School of Medicine, Hangzhou, 310015, China.
  • 6. Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 7. Department of Orthopaedics, the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. [email protected].
  • 8. Department of Geriatrics, Zhejiang Provincial Key Lab of Geriatrics, Zhejiang Hospital, Hangzhou, 310030, China. [email protected].
  • # Contributed equally.
PMID: 38307877 DOI: 10.1038/s41467-024-45315-x
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.

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