Fine-tune of intrinsic ERK activity by extrinsic BMP signaling in mouse embryonic stem cells.

Embryonic stem (ES) cells hold great promise in regenerative medicine and it is an urgent task to understand the underlying molecular mechanisms that control ES cell fate choice between self-renewal and differentiation. In mouse ES cells, extrinsic leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) signaling pathways play pivotal roles in maintaining the self-renewal status under serum and feeder free culture conditions. Intrinsic extracellular-signal regulated kinase (ERK) activity is also important in determining mouse ES cell fate-low ERK activity keeps mouse ES cell self-renewal while high ERK activity drives differentiation. We recently found that while LIF signaling augments ERK activity, BMP signaling inhibits ERK activity in mouse ES cells via direct upregulation of an ERK phosphatase-dual-specificity phosphatase 9. The cooperative effects of LIF and BMP signaling keep appropriate ERK activity and maintain mouse ES cell self-renewal (Li et al., 2012). These findings shed light on how extrinsic signals converge to intrinsic signaling molecules to regulate cell fate determination. This perspective summarizes our recent new findings and discusses the current unsolved questions and future directions.