Abstract：
: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.
journal_name
Cell Stem Celljournal_title
Cell stem cellauthors
Baumgartner C,Toifl S,Farlik M,Halbritter F,Scheicher R,Fischer I,Sexl V,Bock C,Baccarini Mdoi
10.1016/j.stem.2018.05.003subject
Has Abstractpub_date
2018-06-01 00:00:00pages
879-892.e6issue
6eissn
1934-5909issn
1875-9777pii
S1934-5909(18)30221-2journal_volume
22pub_type
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