Submitted November 24, 2008
Accepted June 28, 2009
M-CSF elevates c-Fos and phospho-C/EBP
(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification
Graham D. Jack, Li Zhang, and Alan D. Friedman*
Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, United States
* Corresponding author; email: afriedm2{at}jhmi.edu.
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 G-CSF and 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 proto-types for additional cytokines that also influence immature myeloid cells. G-CSF specifically activated STAT3 and induced SHP2 phosphorylation, whereas M-CSF preferentially activated PLC
2 and thereby ERK to stabilize c-Fos and stimulate C/EBP
(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/EBP phosphorylation and formation of CFU-M. SHP2 inhibition reduced ERK activation in G-CSF but not M-CSF and reduced CFU-G, 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/EBP(S21), which may directly interact to favor monopoiesis, whereas G-CSF activates STAT3 and SHP2, potentially shifting the balance to granulopoiesis via gene induction by C/EBP homodimers and via effects of SHP2 on regulators besides ERK.
