The combination of leukaemia inhibitory factor (LIF) and serum is sufficient to maintain embryonic stem cell (ESC) self-renewal. On page 1136, Cecilia Annerén and colleagues now provide further insight into the molecular mechanisms regulating this process. Previous studies have shown that LIF activates gp130; this signal transducer then activates – among others – Src family kinase (SFK) signalling pathways. Focusing on the SFK Yes, Annerén and coworkers identify a network of signalling events that ensure sustained ESC self-renewal in response to LIF. Direct interaction of the Yes SH2 domain with gp130 activates the kinase and recruits the Yes-associated protein YAP. This, in turn, results in the tyrosine phosphorylation of YAP and its translocation to the nucleus. There it acts as a transcriptional co-activator by binding to TEAD2, a member of the TEA domain protein family. Formation of the YAP–TEAD2 complex leads to increased transcription of Oct-3/4 and Nanog, thereby promoting ESC self-renewal. In addition, this system seems to be carefully balanced by an autoregulatory loop to ensure the proper maintenance of cell fate. The authors show that overexpression of Nanog substantially decreases TEAD2-dependent transcriptional activity through an as-yet-unknown mechanism.
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