2. Academic Validation
  3. Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma

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

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. zenglh@zucc.edu.cn.
  • 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. xiwu@zju.edu.cn.
  • 7 Department of Orthopaedics, the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. xiwu@zju.edu.cn.
  • 8 Department of Geriatrics, Zhejiang Provincial Key Lab of Geriatrics, Zhejiang Hospital, Hangzhou, 310030, China. wangjr@zju.edu.cn.
  • # 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.

Figures
Products