Role of Erk1/2 signaling in the regulation of neutrophil versus monocyte development in response to G-CSF and M-CSF
| Autor: | Nan Hu, Fan Dong, Yaling Qiu |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Macrophage colony-stimulating factor
Myeloid MAP Kinase Signaling System Neutrophils Cellular differentiation Apoptosis Bone Marrow Cells Biology Biochemistry Granulopoiesis Gene Expression Regulation Enzymologic Monocytes Cell Line Mice Granulocyte Colony-Stimulating Factor medicine Animals Cell Lineage Molecular Biology Myelopoiesis Monocyte Macrophage Colony-Stimulating Factor Cell Biology Hematopoietic Stem Cells Cell biology Haematopoiesis medicine.anatomical_structure Mutation Cytokines Tyrosine RNA Interference Signal transduction Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 290(40) |
| ISSN: | 1083-351X |
| Popis: | Lineage specification in the hematopoietic system depends on the expression of lineage specific transcription factors. However, the role of hematopoietic cytokines in this process has been controversial and little is known about the intracellular signaling mechanisms by which cytokines instruct lineage choice. G-CSF and M-CSF are two lineage-specific cytokines that play a dominant role in granulopoiesis and monopoiesis, respectively. We show here that a G-CSFR mutant in which tyrosine 729 had been mutated to phenylalanine (Y729F) promoted monocyte rather than neutrophil development in myeloid precursors, which was associated with prolonged activation of Erk1/2 and augmented activation of downstream targets c-Fos and Egr1. Inhibition of Erk1/2 activation or knockdown of c-Fos or Egr1 largely rescued neutrophil development in cells expressing G-CSFR Y729F. We also show that M-CSF, but not G-CSF, stimulated strong and sustained activation of Erk1/2 in mouse lineage marker negative (Lin(-)) bone marrow cells. Significantly, inhibition of Erk1/2 signaling in these cells favored neutrophil over monocyte development in response to M-CSF. Thus, prolonged Erk1/2 activation resulted in monocyte development following G-CSF induction whereas inhibition of Erk1/2 signaling promoted neutrophil development at the expense of monocyte formation in response to M-CSF. These results reveal an important mechanism by which G-CSF and M-CSF instruct neutrophil versus monocyte lineage choice, i.e. differential activation of Erk1/2 pathway. |
| Databáze: | OpenAIRE |
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