Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38307877.
- Also identified by DOI 10.1038/s41467-024-45315-x and PMC identifier 10837140.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Aberrant activation of sonic hedgehog (SHH) signaling and its effector transcriptional factor GLI1 are essential for oncogenesis of SHH-dependent medulloblastoma (MB<sub>SHH</sub>) 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, Gli1<sup>S941E</sup> loss-of-function knock-in significantly reduces the incidence and severity of smoothened-M2 transgene-induced spontaneous MB<sub>SHH</sub>, whereas Gli1<sup>S941A</sup> 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 MB<sub>SHH</sub>. 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 MB<sub>SHH</sub> and BCC.
Medical subject headings
- Cerebellar Neoplasms
- Medulloblastoma