Casein kinase 1α as a regulator of wnt-driven cancer

Chen Shen, Anmada Nayak, Ricardo A. Melendez, Daniel T. Wynn, Joshua Jackson, Ethan Lee, Yashi Ahmed, David J. Robbins

Research output: Contribution to journalReview article

Abstract

Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that drive cancer growth. We then discuss the roles of the established negative Wnt regulator, casein kinase 1α (CK1α), in Wnt signaling. Although the study of CK1α has been ongoing for several decades, the bulk of such research has focused on how it phosphorylates and regulates its various substrates. We focus here on what is known about the mechanisms controlling CK1α, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1α activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1α activators, relative to other classes of Wnt inhibitors, is their reduced on-target toxicity, overcoming one of the major impediments to developing a clinically relevant Wnt inhibitor. Therefore, we also discuss mechanisms that regulate CK1α steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1α activators.

Original languageEnglish (US)
Article number5940
Pages (from-to)1-16
Number of pages16
JournalInternational journal of molecular sciences
Volume21
Issue number16
DOIs
StatePublished - Aug 2 2020

Keywords

  • Cancer
  • CK1α
  • Kinase agonists
  • Review
  • Targeted therapies
  • Wnt

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    Shen, C., Nayak, A., Melendez, R. A., Wynn, D. T., Jackson, J., Lee, E., Ahmed, Y., & Robbins, D. J. (2020). Casein kinase 1α as a regulator of wnt-driven cancer. International journal of molecular sciences, 21(16), 1-16. [5940]. https://doi.org/10.3390/ijms21165940