Macrophage colony-stimulating factor promotes cell survival through Akt/protein kinase B

The signaling pathways activated by the macrophage colony-stimulating facto r (M-CSF) to promote survival of monocyte and macrophage lineage cells are not well established. In an effort to elucidate these pathways, we have use d two cell types responsive to M-CSF: NIH 3T3 fibroblasts genetically engin eered to express human M-CSF receptors (3T3-FMS cells) and human monocytes, M-CSF treatment induced M-CSF receptor tyrosine phosphorylation and recrui tment of the p85 subunit of phosphatidylinositol 3-kinase (PI3K) to these r eceptors, These M-CSF receptor events correlated with activation of the ser ine/threonine kinase Akt. To clarify that PI3K products activate Akt in res ponse to M-CSF, NIH 3T3 fibroblasts expressing mutant human M-CSF receptors (3T3-FMS(Y809F)) that fail to activate Ras in response to M-CSF also exhib it increased Akt kinase activity in response to M-CSF challenge. Furthermor e, Akt appears to be the primary regulator of survival in 3T3-FMS cells, as transfection of genes encoding dominant-negative Akt isoforms into these f ibroblasts blocked M-CSF-induced survival. In normal human monocytes, M-CSF increased the levels of tyrosine-phosphorylated proteins and induced Akt a ctivation in a PI3K-dependent manner. The PI3K inhibitor LY294002 blocked M -CSF-mediated monocyte survival, an effect that was partially restored by c aspase-9 inhibitors. These data suggest that M-CSF may induce cell survival through Akt-induced suppression of caspase-9 activation.