Phosphorylation of OTUB1 at Tyr 26 stabilizes the mTORC1 component, Raptor

Raptor plays a critical role in mTORC1 signaling. High expression of Raptor is associated with resistance of cancer cells to PI3K/mTOR inhibitors. Here, we found that OTUB1-stabilized Raptor in a non-canonical manner. Using biochemical assays, we found that the tyrosine 26 residue (Y26) of OTUB1 played a critical role in the interaction between OTUB1 and Raptor. Furthermore, non-receptor tyrosine kinases (Src and SRMS kinases) induced phosphorylation of OTUB1 at Y26, which stabilized Raptor. Interestingly, phosphorylation of OTUB1 at Y26 did not affect the stability of other OTUB1-targeted substrates. However, dephosphorylation of OTUB1 destabilized Raptor and sensitized cancer cells to anti-cancer drugs via mitochondrial reactive oxygen species-mediated mitochondrial dysfunction. Furthermore, we detected high levels of phospho-OTUB1 and Raptor in samples of patients with renal clear carcinoma. Our results suggested that regulation of OTUB1 phosphorylation may be an effective and selective therapeutic target for treating cancers via down-regulation of Raptor.

Automated summary

Raptor plays a critical role in mTORC1 signaling. OTUB1 stabilizes Raptor in a non-canonical manner, and the tyrosine 26 residue of OTUB1 is crucial for the interaction between OTUB1 and Raptor. Non-receptor tyrosine kinases induce phosphorylation of OTUB1 at Y26, leading to Raptor stabilization. Dephosphorylation of OTUB1 destabilizes Raptor and sensitizes cancer cells to drugs via mitochondrial dysfunction. Phospho-OTUB1 and Raptor are highly expressed in renal clear carcinoma samples, suggesting that targeting OTUB1 phosphorylation could be an effective therapeutic strategy for cancer treatment.