M-CSF elevates c-Fos and phospho-C/EBPα(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification
- 3 September 2009
- journal article
- Published by American Society of Hematology in Blood
- Vol. 114 (10), 2172-2180
- https://doi.org/10.1182/blood-2008-11-191536
Abstract
The role of hematopoietic cytokines in lineage commitment remains uncertain. To gain insight into the contribution of cytokine signaling to myeloid lineage specification, we compared granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) signaling in Ba/F3 cells expressing both the G-CSF and M-CSF receptors and in lineage-negative murine marrow cells. G-CSF and M-CSF serve as prototypes for additional cytokines that also influence immature myeloid cells. G-CSF specifically activated signal transducer and activator of transcription 3 and induced Src homology region 2 domain-containing phosphatase 2 (SHP2) phosphorylation, whereas M-CSF preferentially activated phospholipase Cγ2, and thereby extracellular signal-regulated kinase (ERK), to stabilize c-Fos and stimulate CCAAT/enhancer-binding protein (C/EBP)α(S21) phosphorylation. In contrast, activation of Jun kinase or c-Jun was similar in response to either cytokine. Inhibition of ERK prevented induction of c-Fos by M-CSF and reduced C/EBPα phosphorylation and formation of colony-forming unit–monocytes. SHP2 inhibition reduced ERK activation in G-CSF, but not M-CSF, and reduced colony-forming unit–granulocytes, underscoring divergent pathways to ERK activation. Phorbol ester mimicked the effect of M-CSF, activating ERK independent of SHP2. In summary, M-CSF activates ERK more potently than G-CSF, and thereby induces higher levels of c-Fos and phospho-C/EBPα(S21), which may directly interact to favor monopoiesis, whereas G-CSF activates signal transducer and activator of transcription 3 and SHP2, potentially shifting the balance to granulopoiesis via gene induction by C/EBPα homodimers and via effects of SHP2 on regulators besides ERK.Keywords
This publication has 53 references indexed in Scilit:
- C/EBPα:AP-1 leucine zipper heterodimers bind novel DNA elements, activate the PU.1 promoter and direct monocyte lineage commitment more potently than C/EBPα homodimers or AP-1Oncogene, 2007
- C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitmentBlood, 2007
- Activation of mitogen-activated protein kinase kinase (MEK)/extracellular signal–regulated kinase (ERK) signaling pathway is involved in myeloid lineage commitmentBlood, 2007
- The Transcriptional Repressor GFI-1 Antagonizes PU.1 Activity through Protein-Protein InteractionPublished by Elsevier BV ,2007
- STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophilsBlood, 2006
- Src family kinases are important negative regulators of G-CSF-dependent granulopoiesisBlood, 2006
- C/EBPα directs monocytic commitment of primary myeloid progenitorsBlood, 2006
- Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1Nature Genetics, 2004
- Site-Specific Incorporation of a Phosphotyrosine Mimetic Reveals a Role for Tyrosine Phosphorylation of SHP-2 in Cell SignalingMolecular Cell, 2001
- IL3-dependent mouse clones that express B-220 surface antigen, contain ig genes in germ-line configuration, and generate B lymphocytes in vivoCell, 1985