{Reference Type}: Journal Article
{Title}: Ceramide-induced cleavage of GPR64 intracellular domain drives Ewing sarcoma.
{Author}: Suvarna K;Jayabal P;Ma X;Wang H;Chen Y;Weintraub ST;Han X;Houghton PJ;Shiio Y;
{Journal}: Cell Rep
{Volume}: 43
{Issue}: 8
{Year}: 2024 Aug 27
暂无{DOI}: 10.1016/j.celrep.2024.114497
{Abstract}: 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.