An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion

• DOI: 10.1016/j.stem.2018.05.003
• Publication Date: 2018-05-24T14:48:25Z
• Authors: Christian Baumgar...; Stefanie Toifl; Matthias Farlik; Florian Halbritter; Ruth Scheicher; Irmgard Fischer; Veronika Sexl; Christoph Bock; Manuela Baccarini
• Keywords: Hematopoietic stem cell

Hematopoietic stem cells (HSCs) sustain hematopoiesis throughout life. HSCs exit dormancy to restore hemostasis in response stressful events, such as acute blood loss, and must return a quiescent state prevent their exhaustion resulting bone marrow failure. HSC activation is driven part through the phosphatidylinositol 3-kinase (PI3K)/AKT/mTORC1 signaling pathway, but less known about cell-intrinsic pathways that control dormancy. Here, we delineate an ERK-dependent, rate-limiting feedback mechanism controls fitness re-entry into quiescence. We show MEK/ERK PI3K are synchronously activated during emergency phosphorylation of MEK1 by ERK counterbalances AKT/mTORC1 activation. Genetic or chemical ablation this loop tilts balance between activation, increasing differentiated cell output accelerating exhaustion. These results suggest MEK inhibitors developed for cancer therapy may find additional utility controlling