Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-γ2 and MAP kinases ERK1 and ERK2

Macrophage colony-stimulating factor (M-CSF) has been found to be involved in multiple developmental processes, especially production of cells belonging to the mononuclear phagocyte system. The decision of myeloid progenitor cells to commit to differentiation depends on activation levels of the mitogen-activated protein kinases MAPK), ERK1 and ERK2. Using the murine myeloid progenitor cell line FDFms, we show here that persistent activity of Srcfamily kinases SFK) is necessary for FDFms cell differentiation to macrophages in response to MCSF. Chemical inhibition of SFK blocked FDFms cell differentiation while it caused strong inhibition of the late phosphorylation of phospholipase C PLC)gamma 2 and MAPK. The PLC inhibitor U73122, previously shown to block MCSFinduced differentiation, strongly decreased longterm MAPK phosphorylation. Interestingly, inhibiting SFK with SU6656 or the MAPK kinases MEK with U0126 significantly impaired development of mononuclear phagocytes in cultures of mouse bone marrow cells stimulated with MCSF. Collectively, results support a model in which SFK are required for sustained PLC activity and MAPK activation above threshold required for commitment of myeloid progenitors to macrophage differentiation.