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Actin/BMP signaling controls embryonic stem cell fate and morphogenesis in zebrafish embryos through SMAD4-mediated responses, but the regulation of SMAD4 activity is not well understood.Here we performed a gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of Actin/BMP signaling.USP4 was found to directly interact with SMAD4 and specifically remove SMAD4 monoubiquitination, which we found was triggered by regulatory (R)-SMAD recruited E3 ligase SMURF2 upon signal activation.SMURF2 induced SMAD4 monoubiquitination prevented R-SMAD-SMAD4 complex from over-activation and its subsequent removal by USP4 empowered SMAD4 activity and facilitated a rapid re-use of SMAD4 molecule.