ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal

•ERK1 phosphorylates Nanog and inhibits Nanog transactivation.•Phosphorylation of Nanog by ERK1 induces ES cell differentiation.•Phosphorylation of Nanog by ERK1 decreases Nanog stability.•Phosphorylation induces binding of FBXW8 with Nanog reducing Nanog protein stability.

Nanog regulates human and mouse embryonic stem (ES) cell self-renewal activity. Activation of ERKs signaling negatively regulates ES cell self-renewal and induces differentiation, but the mechanisms are not understood. We found that ERK1 binds and phosphorylates Nanog. Activation of MEK/ERKs signaling and phosphorylation of Nanog inhibit Nanog transactivation, inducing ES cell differentiation. Conversely, suppression of MEK/ERKs signaling enhances Nanog transactivation to inhibit ES cell differentiation. We observed that phosphorylation of Nanog by ERK1 decreases Nanog stability through ubiquitination-mediated protein degradation. Further, we found that this phosphorylation induces binding of FBXW8 with Nanog to reduce Nanog protein stability. Overall, our results demonstrated that ERKs-mediated Nanog phosphorylation plays an important role in self-renewal of ES cells through FBXW8-mediated Nanog protein stability.