Proposed model for the role of differential STAT3 phosphorylation in regulating stem cell fates. In mouse embryonic stem cells (mESCs), activation of leukemia inhibitory factor (LIF)/JAK signaling induces phosphorylation of STAT3 Y705 to maintain self-renewal. Upon withdrawal of LIF from the culture environment, mESCs differentiate into mouse epiblast stem cells (mEpiSCs) concomitant with a switch from LIF/JAK-mediated phosphorylation of Y705 to FGF/Erk-mediated phosphorylation of S727. In the mEpiSC stage, STAT3 pS727 promotes neural commitment and secures this differentiation-primed state by inhibiting JAK/pY705-induced reprogramming. Abbreviations: FGF, fibroblast growth factor; LIF, leukemia inhibitory factor; mESC, mouse embryonic stem cell; mEpiSC, mouse epiblast stem cell.