磷酸化
mTORC1型
癌症研究
激酶
生物
脱磷
细胞生物学
原癌基因酪氨酸蛋白激酶Src
受体酪氨酸激酶
酪氨酸激酶
信号转导
蛋白激酶B
磷酸酶
作者
Seung Un Seo,Seon Min Woo,Min Wook Kim,Eun Woo Lee,Kyoung‐jin Min,Taeg Kyu Kwon
标识
DOI:10.1038/s41418-022-01047-3
摘要
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.
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