Journal
STEM CELL REPORTS
Volume 5, Issue 4, Pages 633-646Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2015.08.006
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Funding
- Deutsche Jose Carreras Leukamie-Stiftung [DJCLS F 10/03]
- German Cancer Aid (Deutsche Krebshilfe) [108688, 108400]
- LOEWE [IIIL4-518/17.004, IIIL6-518/75.004]
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FLT3 and c-KIT are crucial regulators of hematopoietic stem and progenitor cells. We investigated the role of STS1 and STS2 on FLT3 and cKIT phosphorylation, activity, and function in normal and stress-induced hematopoiesis. STS1/STS2-deficient mice show a profound expansion of multipotent progenitor and lymphoid primed multipotent progenitor cells with elevated colony-forming capacity. Although long-term hematopoietic stem cells are not increased in numbers, lack of STS1 and STS2 significantly promotes long-term repopulation activity, demonstrating a pivotal role of STS1/STS2 in regulating hematopoietic stem and progenitor cell fitness. Biochemical analysis identified STS1/STS2 as direct phosphatases of FLT3 and c-KIT. Loss of STS1/STS2 induces hyperphosphorylation of FLT3, enhances AKT signaling, and confers a strong proliferative advantage. Therefore, our study reveals that STS1 and STS2 may serve as novel pharmaceutical targets to improve hematopoietic recovery after bone marrow transplantation.
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