The Phosphatases STS1 and STS2 Regulate Hematopoietic Stem and Progenitor Cell Fitness
| Autor: | Srinivasa Rao Bandi, Katja Jakobi, Nick Carpino, Ramona Gomes Fernandes, Jing Zhang, Olesya Vakhrusheva, Hubert Serve, Özlem Demirel, Lars Rönnstrand, Michael A. Rieger, Julhash U. Kazi, Christian Brandts, Astrid Eichler |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Receptors
Antigen T-Cell Stem cell factor Biology Biochemistry CXCR4 Article Cell Line Mice Genetics Animals Phosphorylation Progenitor cell lcsh:QH301-705.5 Cells Cultured Cell Proliferation Interleukin 3 Mice Knockout lcsh:R5-920 Cell Biology Hematopoietic Stem Cells Hematopoiesis Cell biology Mice Inbred C57BL Endothelial stem cell Proto-Oncogene Proteins c-kit Haematopoiesis fms-Like Tyrosine Kinase 3 lcsh:Biology (General) Protein Tyrosine Phosphatases Stem cell lcsh:Medicine (General) Developmental Biology Adult stem cell |
| Zdroj: | Stem Cell Reports, Vol 5, Iss 4, Pp 633-646 (2015) Stem Cell Reports |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2015.08.006 |
| Popis: | Summary FLT3 and c-KIT are crucial regulators of hematopoietic stem and progenitor cells. We investigated the role of STS1 and STS2 on FLT3 and c-KIT 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. Graphical Abstract Highlights • Hematopoietic stem cells lacking STS1/STS2 display significantly enhanced fitness • STS1 and STS2 are phosphatases of FLT3 and c-KIT • Lack of STS1/STS2 activates FLT3 and downstream signaling Brandts and colleagues report a novel mechanism of hematopoietic stem and progenitor cell regulation by phosphatases. Mice lacking STS1 and STS2 show a significant increase in hematopoietic stem cell fitness and long-term repopulation capacity as well as enhanced progenitor cell proliferation. The authors identify STS1/STS2 as direct phosphatases of FLT3, regulating downstream signaling and cell proliferation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|