Claspin is required for growth recovery from serum starvation through regulating the PI3K-PDK1-mTOR pathway
Claspin is required for growth recovery from serum starvation through regulating the PI3K-PDK1-mTOR pathway
复制标题
Claspin 是通过调节 PI3K-PDK1-mTOR 通路从血清饥饿中恢复生长所必需的
DOI：
10.1101/2022.01.21.475743
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Masai Hisao
中科院分区：
文献类型：
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作者：
Yang Chi-Chun;Masai Hisao
Claspin作为细胞对复制应激反应的中介，在DNA复制调控中发挥着多种重要作用，它是一个促进复制叉进程的完整复制叉因子，也是一个通过募集Cdc7激酶促进起始的因子。在这里，我们报道了Claspin在血清饥饿后生长恢复中的新作用，这需要激活PI3K -PDK1-Akt-mTOR通路。在缺乏Claspin的情况下，细胞不会进入S期，最终以ROS-和p53依赖的方式部分死亡。Claspin直接与PI3K和mTOR相互作用，是激活PI3K- pdk1 -mTOR以及mTOR下游因子p70S6K和4EBP1所必需的，但在血清饥饿恢复过程中不参与p38 MAPK级联反应。PDK1与Claspin物理相互作用，特别是与CKBD相互作用，其方式依赖于后者蛋白的磷酸化，并且是mTOR与Claspin相互作用所必需的。因此，Claspin通过激活mTOR通路，作为营养诱导的增殖/存活信号的关键调节因子发挥了新的作用。结果还表明，Claspin可能作为一种共同的介质，接收来自不同pi3k相关激酶的信号，并将其传递给特定的下游激酶。
Claspin plays multiple important roles in regulation of DNA replication as a mediator for the cellular response to replication stress, an integral replication fork factor that facilitates replication fork progression and a factor that promotes initiation by recruiting Cdc7 kinase. Here, we report a novel role of Claspin in growth recovery from serum starvation, which requires the activation of PI3 kinase (PI3K)-PDK1-Akt-mTOR pathways. In the absence of Claspin, cells do not proceed into S phase and eventually die partially in a ROS- and p53-dependent manner. Claspin directly interacts with PI3K and mTOR, and is required for activation of PI3K-PDK1-mTOR and for that of mTOR downstream factors, p70S6K and 4EBP1, but not for p38 MAPK cascade during the recovery from serum starvation. PDK1 physically interacts with Claspin, notably with CKBD, in a manner dependent on phosphorylation of the latter protein, and is required for interaction of mTOR with Claspin. Thus, Claspin plays a novel role as a key regulator for nutrition-induced proliferation/survival signaling by activating the mTOR pathway. The results also suggest a possibility that Claspin may serve as a common mediator that receives signals from different PI3K-related kinases and transmit them to specific downstream kinases.