The four members of the vertebrate CPEB family of RNA-binding proteins share similar RNA-binding domains by which they regulate the translation of CPE-containing mRNAs, thereby controlling cell cycle and differentiation or synaptic plasticity. However, the N-terminal domains of CPEBs are distinct and contain specific regulatory post-translational modifications that presumably differentially integrate extracellular signals. Here we show that CPEB4 activity is regulated by ERK2- and Cdk1-mediated hyperphosphorylation. These phosphorylation events additively activate CPEB4 in M-phase by maintaining it in its monomeric state. In contrast, unphosphorylated CPEB4 phase separates into inactive, liquid-like droplets through its intrinsically disordered regions in the N-terminal domain. This dynamic and reversible regulation of CPEB4 is coordinated with that of CPEB1 through Cdk1, which inactivates CPEB1 while activating CPEB4, thereby integrating phase-specific signal transduction pathways to regulate cell cycle progression.
Keywords: CPEB; RNA-binding protein; cell biology; cell cycle; instrinsically disordered region; liquid-like droplets; mRNA translation; xenopus.