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Ceramide-induced cleavage of GPR64 intracellular domain drives Ewing sarcoma.

Kruthi Suvarna | Panneerselvam Jayabal | Xiuye Ma | Hu Wang | Yidong Chen | Susan T Weintraub | Xianlin Han | Peter J Houghton | Yuzuru Shiio
Cell reports | 2024

Ewing sarcoma is a cancer of bone and soft tissue in children and young adults primarily driven by the EWS-FLI1 fusion oncoprotein, which has been undruggable. Here, we report that Ewing sarcoma depends on secreted sphingomyelin phosphodiesterase 1 (SMPD1), a ceramide-generating enzyme, and ceramide. We find that G-protein-coupled receptor 64 (GPR64)/adhesion G-protein-coupled receptor G2 (ADGRG2) responds to ceramide and mediates critical growth signaling in Ewing sarcoma. We show that ceramide induces the cleavage of the C-terminal intracellular domain of GPR64, which translocates to the nucleus and restrains the protein levels of RIF1 in a manner dependent on SPOP, a substrate adaptor of the Cullin3-RING E3 ubiquitin ligase. We demonstrate that both SMPD1 and GPR64 are transcriptional targets of EWS-FLI1, indicating that SMPD1 and GPR64 are EWS-FLI1-induced cytokine-receptor dependencies. These results reveal the SMPD1-ceramide-GPR64 pathway, which drives Ewing sarcoma growth and is amenable to therapeutic intervention.

Pubmed ID: 39024100 RIS Download

Antibodies used in this publication

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: U01 CA283414
  • Agency: NCI NIH HHS, United States
    Id: R01 CA283414
  • Agency: NCI NIH HHS, United States
    Id: P01 CA165995
  • Agency: NIA NIH HHS, United States
    Id: P30 AG013319
  • Agency: NIH HHS, United States
    Id: S10 OD030371
  • Agency: NIA NIH HHS, United States
    Id: P30 AG044271
  • Agency: NCI NIH HHS, United States
    Id: P30 CA054174

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