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

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 () and Jirong Wang ()
Additional contact information
Ling-Hui Zeng: Hangzhou City University School of Medicine
Chao Tang: Zhejiang University School of Medicine
Minli Yao: Zhejiang University School of Medicine
Qiangqiang He: Zhejiang University School of Medicine
Meiyu Qv: Hangzhou City University School of Medicine
Qianlei Ren: Hangzhou City University School of Medicine
Yana Xu: Zhejiang University School of Medicine
Tingyu Shen: 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
Chaochun Zou: the Children’s Hospital of Zhejiang University School of Medicine
Xing Ji: Hangzhou City University School of Medicine
Ximei Wu: Zhejiang University School of Medicine
Jirong Wang: Zhejiang Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-45315-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45315-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-45315-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().