Department of Pathology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
Mol Cell. 2011 Oct 21;44(2):317-24. doi: 10.1016/j.molcel.2011.09.005.
DEPTOR is a recently identified inhibitor of the mTOR kinase that is highly regulated at the posttranslational level. In response to mitogens, we found that DEPTOR was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the F box protein βTrCP, with consequent proteasomal degradation of DEPTOR. Phosphorylation of the βTrCP degron in DEPTOR is executed by CK1α after a priming phosphorylation event mediated by either the mTORC1 or mTORC2 complexes. Blocking the βTrCP-dependent degradation of DEPTOR via βTrCP knockdown or expression of a stable DEPTOR mutant that is unable to bind βTrCP results in mTOR inhibition. Our findings reveal that mTOR cooperates with CK1α and βTrCP to generate an auto-amplification loop to promote its own full activation. Moreover, our results suggest that pharmacologic inhibition of CK1 may be a viable therapeutic option for the treatment of cancers characterized by activation of mTOR-signaling pathways.
DEPTOR 是一种新发现的 mTOR 激酶抑制剂，其在翻译后水平受到高度调控。在有丝分裂原的刺激下，我们发现 DEPTOR 上的三个丝氨酸残基被迅速磷酸化，从而促进了 F 盒蛋白 βTrCP 的结合和泛素化，导致 DEPTOR 的蛋白酶体降解。DEPTOR 中 βTrCP 降解序列的磷酸化是由 CK1α 执行的，该磷酸化是由 mTORC1 或 mTORC2 复合物介导的初始磷酸化事件触发的。通过βTrCP 敲低或表达不能与βTrCP 结合的稳定 DEPTOR 突变体来阻断 DEPTOR 的 βTrCP 依赖性降解，会导致 mTOR 抑制。我们的研究结果表明，mTOR 与 CK1α 和 βTrCP 合作，形成自动放大环，以促进其自身的完全激活。此外，我们的研究结果表明，抑制 CK1 的药理学可能是治疗以 mTOR 信号通路激活为特征的癌症的可行治疗选择。
