An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion.
An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion.
复制标题
DOI：
10.1016/j.stem.2018.05.003
复制
发表时间：
2018-06-01
期刊：
影响因子：
23.9
通讯作者：
Baccarini M
中科院分区：
文献类型：
--
作者：
Baumgartner C;Toifl S;Farlik M;Halbritter F;Scheicher R;Fischer I;Sexl V;Bock C;Baccarini M
造血干细胞（HSCs）维持整个生命的造血。HSC退出休眠以恢复止血以响应应激事件，例如急性失血，并且必须返回到静止状态以防止它们的耗尽和导致的骨髓衰竭。HSC活化部分通过磷脂酰肌醇3-激酶（PI 3 K）/AKT/mTORC 1信号通路驱动，但对控制HSC休眠的细胞内在通路知之甚少。在这里，我们描绘了一个ERK依赖的，限速反馈机制，控制HSC健身和他们重新进入静止。我们发现，MEK/ERK和PI 3 K通路在紧急造血过程中同步激活，并且激活的ERK对MEK 1的反馈磷酸化抵消了AKT/mTORC 1的激活。遗传或化学消融这个反馈回路，使HSC休眠和激活之间的平衡倾斜，增加分化的细胞输出并加速HSC耗尽。这些结果表明，开发用于癌症治疗的MEK抑制剂可能在控制HSC活化方面发现额外的效用。MEK/ERK和AKT/mTORC 1在造血过程中可逆激活MEK 1在应激造血过程中防止HSC耗尽ERK对MEK 1的反馈磷酸化限制了ERK介导的MEK 1磷酸化使激活的HSC恢复静止Baccarini和同事确定了一种细胞内在反馈机制，该机制限制了造血干细胞激活过程中MEK/ERK和AKT/mTORC 1信号的强度。该机制取决于活化的ERK对MEK 1的负反馈磷酸化，并且是防止HSC耗竭所必需的。
Hematopoietic stem cells (HSCs) sustain hematopoiesis throughout life. HSCs exit dormancy to restore hemostasis in response to stressful events, such as acute blood loss, and must return to a quiescent state to prevent their exhaustion and resulting bone marrow failure. HSC activation is driven in part through the phosphatidylinositol 3-kinase (PI3K)/AKT/mTORC1 signaling pathway, but less is known about the cell-intrinsic pathways that control HSC dormancy. Here, we delineate an ERK-dependent, rate-limiting feedback mechanism that controls HSC fitness and their re-entry into quiescence. We show that the MEK/ERK and PI3K pathways are synchronously activated in HSCs during emergency hematopoiesis and that feedback phosphorylation of MEK1 by activated ERK counterbalances AKT/mTORC1 activation. Genetic or chemical ablation of this feedback loop tilts the balance between HSC dormancy and activation, increasing differentiated cell output and accelerating HSC exhaustion. These results suggest that MEK inhibitors developed for cancer therapy may find additional utility in controlling HSC activation. MEK/ERK and AKT/mTORC1 are reversibly activated during hematopoiesis MEK1 prevents HSC exhaustion during stress hematopoiesis Feedback phosphorylation of MEK1 by ERK limits AKT/mTORC1 activation ERK-mediated MEK1 phosphorylation returns activated HSCs to quiescence Baccarini and colleagues identify a cell-intrinsic feedback mechanism limiting the strength of MEK/ERK and AKT/mTORC1 signals during the activation of hematopoietic stem cells. The mechanism hinges on the negative feedback phosphorylation of MEK1 by activated ERK and is required to prevent HSC exhaustion.
登录
查看更多内容
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
64.5
作者：
Bernitz, Jeffrey M.;Kim, Huen Suk;MacArthur, Ben;Sieburg, Hans;Moore, Kateri
通讯作者：
Moore, Kateri
DOI：
10.1038/nrm3772
发表时间：
2014-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Busch, Katrin;Klapproth, Kay;Rodewald, Hans-Reimer
通讯作者：
Rodewald, Hans-Reimer
影响因子：
4.6
作者：
Bigarella, Carolina L.;Liang, Raymond;Ghaffari, Saghi
通讯作者：
Ghaffari, Saghi