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Zeta‐chain‐associated protein kinase‐70 (Zap70), a Syk family tyrosine kinase, has been reported to be present exclusively in normal T‐cells, natural killer cells, and B cells, serving as a pivotal regulator of antigen‐mediated receptor signaling and development. In this study, we report that Zap70 is expressed in undifferentiated mouse embryonic stem cells (mESCs) and may critically regulate self‐renewal and pluripotency in mESCs. We found that Zap70 knocked‐down mESCs (Zap70KD) show sustained self‐renewal and defective differentiation. In addition, we present evidence that the sustained self‐renewal in Zap70KD is associated with enhanced Jak/Stat3 signaling and c‐Myc induction. These altered signaling appears to result from upregulated leukemia inhibitory factor receptor and downregulated src homology region 2 domain containing phosphatase 1 (SHP‐1) phosphatase activity. On the basis of these results, we propose that in undifferentiated mESCs, Zap70 plays important roles in modulating the balance between self‐renewal capacity and pluripotent differentiation ability as a key regulator of the Jak/Stat3/c‐Myc signaling pathway. S tem  C ells  2010; 28:1476–1486.

Zap70 Functions to Maintain Stemness of Mouse Embryonic Stem Cells by Negatively Regulating Jak1/Stat3/c‐Myc Signaling