2. Academic Validation
  3. A CK1 FRET biosensor reveals that DDX3X is an essential activator of CK1ε

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.
Christine Dolde 1,  Joachim Bischof 2,  Simon Grüter 1,  Anna Montada 3,  Jakob Halekotte 4,  Christian Peifer 4,  Hubert Kalbacher 5,  Ulrich Baumann 3,  Uwe Knippschild 2,  Beat Suter 6
Affiliations

Affiliations

  • 1 Institute of Cell Biology, Department of Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland.
  • 2 Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
  • 3 Department of Chemistry, Institute of Biochemistry, University of Cologne, Otto-Fischer-Str. 12-14, 50674 Cologne, Germany.
  • 4 Institute for Pharmaceutical Chemistry, Christian Albrechts University, Gutenbergstraße 76, 24118 Kiel, Germany.
  • 5 Interfaculty Institute of Biochemistry, University of Tübingen, Ob dem Himmelreich 7, 72074 Tübingen, Germany.
  • 6 Institute of Cell Biology, Department of Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland [email protected].
PMID: 29222110 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.

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