Casein Kinase 1? as a Regulator of Wnt-Driven Cancer.

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 1? (CK1?), in Wnt signaling. Although the study of CK1? 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 CK1?, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1? activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1? 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 CK1? steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1? activators.

SUBMITTER: Shen C 

PROVIDER: S-EPMC7460588 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature