PDF(Pubmed)
Abstract：
Mammalian target of rapamycin (mTOR) kinase functions as a central regulator of cell growth and metabolism, and its complexes mTORC1 and mTORC2 phosphorylate distinct substrates. Dysregulation of mTOR signaling is commonly implicated in human diseases, including cancer. Despite three decades of active research in mTOR, much remains to be determined. Here, we demonstrate that prolyl 4-hydroxylase alpha-2 (P4HA2) binds directly to mTOR and hydroxylates one highly conserved proline 2341 (P2341) within a kinase domain of mTOR, thereby activating mTOR kinase and downstream effector proteins (e.g. S6K and AKT). Moreover, the hydroxylation of P2341 strengthens mTOR stability and allows mTOR to accurately recognize its substrates such as S6K and AKT. The growth of lung adenocarcinoma cells overexpressing mTORP2341A is significantly reduced when compared with that of cells overexpressing mTORWT. Interestingly, in vivo cell growth assays show that targeting P4HA2-mTOR significantly suppresses lung adenocarcinoma cell growth. In summary, our study reveals an undiscovered hydroxylation-regulatory mechanism by which P4HA2 directly activates mTOR kinase, providing insights for therapeutically targeting mTOR kinase-driven cancers.
摘要：
哺乳动物雷帕霉素靶蛋白(mTOR)激酶是细胞生长和代谢的中枢调节因子,其复合物mTORC1和mTORC2磷酸化不同的底物。mTOR信号的失调通常与人类疾病有关。包括癌症.尽管对mTOR进行了三十年的积极研究，还有很多事情有待确定。这里,我们证明了脯氨酸4-羟化酶α-2（P4HA2）直接结合mTOR和羟基化一个高度保守的脯氨酸2341（P2341）在mTOR的激酶域内，从而激活mTOR激酶和下游效应蛋白(例如S6K和AKT)。此外，P2341的羟基化增强了mTOR的稳定性，并使mTOR能够准确识别其底物，例如S6K和AKT。与过表达mTORWT的细胞相比，过表达mTORP2341A的肺腺癌细胞的生长显着降低。有趣的是,体内细胞生长测定显示靶向P4HA2-mTOR显著抑制肺腺癌细胞生长。总之,我们的研究揭示了一种未发现的羟基化调节机制，P4HA2通过该机制直接激活mTOR激酶，为治疗靶向mTOR激酶驱动的癌症提供见解。
