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.
Highlights
The evolutionarily conserved Wnt signaling cascade has been extensively studied for over three decades and has been shown to regulate numerous cellular events during development and adult tissue homeostasis, as well as in disease when deregulated [1,2]
We focus on the canonical Wnt signaling pathway, discussing the role of its various critical components in cancer, with a focus on the established negative regulator of Wnt signaling, casein kinase 1α (CK1α)
A number of potent, chemically novel CK1α activators (SSTC3 and SSTC104- see Figure 4), which have significantly improved bioavailability by comparison with pyrvinium, have been described [97,127]. These second-generation CK1α activators bind to CK1α in a manner that is competitive to pyrvinium, suggesting that they bind to a similar site on CK1α [97]
Summary
The evolutionarily conserved Wnt signaling cascade has been extensively studied for over three decades and has been shown to regulate numerous cellular events during development and adult tissue homeostasis, as well as in disease when deregulated [1,2]. Wnt proteins undergo palmitoylation by the membrane-bound O-acyltransferase porcupine (PORCN) in the endoplasmic reticulum (ER) [6,7,8]. This modification promotes Wnt export from the ER and subsequently out of the cell and facilitates its activation and binding to the membrane receptor frizzled (Fzd) [6,7,8,9,10]. We focus on the canonical Wnt signaling pathway, discussing the role of its various critical components in cancer, with a focus on the established negative regulator of Wnt signaling, casein kinase 1α (CK1α)
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