Regulation of cell proliferation by FoxO3a. (Left) Growth factor signals in HSCs of stressed or aged wild-type mice. Growth factor signals activate both AKT-mTOR and MEK-ERK pathways. These pathways cooperatively stimulate cell proliferation, in turn up-regulating Spred2 and CDK inhibitors to oppose proliferation through negative feedback. (Right) Growth factor signals in HSCs of stressed or aged FoxO3a-deficient mice. In the absence of FoxO3a, negative feedback pathways up-regulating Spred2 and p27Kip1 expression and antagonizing proliferation are strongly inhibited in HSCs, and AKT and ERK are hyperactivated, resulting in myeloproliferation.