A CK1 FRET biosensor reveals that DDX3X is an essential activator of CK1ε

J Cell Sci. 2018 Jan 4;131(1):jcs207316. doi: 10.1242/jcs.207316.

Abstract

Casein kinase 1 (CK1) plays central roles in various signal transduction pathways and performs many cellular activities. For many years CK1 was thought to act independently of modulatory subunits and in a constitutive manner. Recently, DEAD box RNA helicases, in particular DEAD box RNA helicase 3 X-linked (DDX3X), were found to stimulate CK1 activity in vitro In order to observe CK1 activity in living cells and to study its interaction with DDX3X, we developed a CK1-specific FRET biosensor. This tool revealed that DDX3X is indeed required for full CK1 activity in living cells. Two counteracting mechanisms control the activity of these enzymes. Phosphorylation by CK1 impairs the ATPase activity of DDX3X and RNA destabilizes the DDX3X-CK1 complex. We identified possible sites of interaction between DDX3X and CK1. While mutations identified in the DDX3X genes of human medulloblastoma patients can enhance CK1 activity in living cells, the mechanism of CK1 activation by DDX3X points to a possible therapeutic approach in CK1-related diseases such as those caused by tumors driven by aberrant Wnt/β-catenin and Sonic hedgehog (SHH) activation. Indeed, CK1 peptides can reduce CK1 activity.

Keywords: Activating kinase subunit; CK1 biosensor; Medulloblastoma; Protein Ser/Thr kinase; RNA helicase DDX3; Wnt signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biosensing Techniques*
  • Casein Kinase I / metabolism*
  • Cerebellar Neoplasms / genetics
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Medulloblastoma / genetics*
  • Mutation
  • Phosphorylation
  • RNA Helicases / genetics
  • RNA Helicases / metabolism*
  • Wnt Signaling Pathway*

Substances

  • Casein Kinase I
  • DDX3X protein, human
  • DEAD-box RNA Helicases
  • RNA Helicases