| First Author | Zeng LH | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 987 |
| PubMed ID | 38307877 | Mgi Jnum | J:345058 |
| Mgi Id | MGI:7581474 | Doi | 10.1038/s41467-024-45315-x |
| Citation | Zeng LH, et al. (2024) Phosphorylation of human glioma-associated oncogene 1 on Ser937 regulates Sonic Hedgehog signaling in medulloblastoma. Nat Commun 15(1):987 |
| abstractText | Aberrant activation of sonic hedgehog (SHH) signaling and its effector transcriptional factor GLI1 are essential for oncogenesis of SHH-dependent medulloblastoma (MB(SHH)) and basal cell carcinoma (BCC). Here, we show that SHH inactivates p38alpha (MAPK14) in a smoothened-dependent manner, conversely, p38alpha 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(S941E) loss-of-function knock-in significantly reduces the incidence and severity of smoothened-M2 transgene-induced spontaneous MB(SHH), whereas Gli1(S941A) 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(SHH). Together, these findings indicate that SHH-induced p38alpha inactivation and subsequent GLI1 dephosphorylation and stabilization in controlling SHH signaling and may provide avenues for future interventions of MB(SHH) and BCC. |
