Phosphorylation of MSX1 controls tumorigenesis and bone development through targeting FBXW7 degradation

The transcription factor MSX1, typically expressed in early development but not in most adult tissues, is often re-activated in various cancers, although its underlying oncogenic mechanisms remain elusive. Here, we found that MSX1 promotes the degradation of FBXW7, an E3 ligase and tumor suppressor, through the CDK1-mediated phosphorylation of MSX1 at Ser136. The phosphorylation mimic MSX1 S136D mutant, but not the dephosphorylated S136A mutant, degrades FBXW7 and results in the accumulation of its substrates, including c-MYC and MCL1, ultimately leading to gastric cancer growth and resistance to apoptosis. As the pMSX1–FBXW7 oncogenic axis was validated in clinical gastric cancer samples, we then developed a therapeutic strategy combining chemotherapy with CDK1 inhibition, which synergistically inhibited the gastric cancer growth. Remarkably, the generated S136A knock-in mouse model showed significant protection against carcinogen-induced gastric tumorigenesis, while also exhibited defective limb and skull dysraphism. Collectively, these findings unraveled the importance of pMSX1–FBXW7 axis for both cancer and mammalian development.