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

ABSTRACT: 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 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^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

SUBMITTER: Zeng LH 

PROVIDER: S-EPMC10837140 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature