M-CSF elevates c-Fos and phospho-C/EBPalpha(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification

Blood. 2009 Sep 3;114(10):2172-80. doi: 10.1182/blood-2008-11-191536. Epub 2009 Jul 8.


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 Cgamma2, and thereby extracellular signal-regulated kinase (ERK), to stabilize c-Fos and stimulate CCAAT/enhancer-binding protein (C/EBP)alpha(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/EBPalpha 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/EBPalpha(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/EBPalpha homodimers and via effects of SHP2 on regulators besides ERK.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • Cell Line
  • Dimerization
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Genes, fos / physiology*
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Granulocyte Precursor Cells / cytology
  • Granulocyte Precursor Cells / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Macrophage Colony-Stimulating Factor / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Mice
  • Monocyte-Macrophage Precursor Cells / cytology
  • Monocyte-Macrophage Precursor Cells / metabolism*
  • Myelopoiesis / drug effects
  • Myelopoiesis / physiology
  • Phospholipase C gamma
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • STAT3 Transcription Factor / metabolism


  • CCAAT-Enhancer-Binding Protein-alpha
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Granulocyte Colony-Stimulating Factor
  • Macrophage Colony-Stimulating Factor
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Phospholipase C gamma