title: CPEB4 is regulated during cell cycle by ERK2/Cdk1-mediated phosphorylation and its assembly into liquid-like droplets.
abstract: 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.
authors: Institute for Research in Biomedicine, Barcelona, Spain.|The Barcelona Institute of Science and Technology, Barcelona, Spain.
authors: Jordina
authors: J
authors: Guillén-Boixet
authors: Institute for Research in Biomedicine, Barcelona, Spain.|The Barcelona Institute of Science and Technology, Barcelona, Spain.
authors: Víctor
authors: V
authors: Buzon
authors: Institute for Research in Biomedicine, Barcelona, Spain.|The Barcelona Institute of Science and Technology, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
authors: Xavier
authors: 0000-0002-8371-4185
authors: X
authors: Salvatella
authors: Institute for Research in Biomedicine, Barcelona, Spain.|The Barcelona Institute of Science and Technology, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
authors: Raúl
authors: 0000-0002-1952-6905
authors: R
authors: Méndez
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle; D005786:Gene Expression Regulation; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009865:Oocytes / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*
chemical_list: C551249:CPEB4 protein, Xenopus; D016601:RNA-Binding Proteins; D029867:Xenopus Proteins; D016203:CDC2 Protein Kinase; D019950:Mitogen-Activated Protein Kinase 1
keywords: CPEB; RNA-binding protein; cell biology; cell cycle; instrinsically disordered region; liquid-like droplets; mRNA translation; xenopus