CPEB4 is regulated during cell cycle by ERK2/Cdk1-mediated phosphorylation and its assembly into liquid-like droplets

Elife. 2016 Nov 1;5:e19298. doi: 10.7554/eLife.19298.

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.

Keywords: CPEB; RNA-binding protein; cell biology; cell cycle; instrinsically disordered region; liquid-like droplets; mRNA translation; xenopus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CDC2 Protein Kinase / metabolism*
  • Cell Cycle*
  • Gene Expression Regulation*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Oocytes / physiology*
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • RNA-Binding Proteins / metabolism*
  • Xenopus
  • Xenopus Proteins / metabolism*

Substances

  • CPEB4 protein, Xenopus
  • RNA-Binding Proteins
  • Xenopus Proteins
  • CDC2 Protein Kinase
  • Mitogen-Activated Protein Kinase 1

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.