Casein Kinase 1α 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 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.

Keywords: CK1α; Wnt; cancer; kinase agonists; review; targeted therapies.

Figure 1

The canonical Wnt signaling pathway. In the Wnt off-state (left), β-catenin, the pivotal transcription coactivator of the Wnt pathway, is degraded by the destruction complex in the cytoplasm. Other Wnt effectors, such as frizzled (Fzd) at the membrane and T cell factor (TCF)/lymphoid enhancer-binding factor 1 (LEF1) transcription factors in the nucleus, are also inhibited to maintain low Wnt activity. In the Wnt on-state (right), Wnt ligands trigger the formation of the signalosome to promote Wnt signal transduction. The function of the destruction complex is inhibited, leading to the stabilization of β-catenin. β-catenin then translocates into the nucleus and binds to TCF/LEF1 to form a transcription complex along with other cofactors to initiate Wnt target transcription. LRP5/6: low-density lipoprotein receptor-related protein 5/6; ZNRF3: E3 ubiquitin ligase zinc- and ring-finger protein 3; RNF43: ring-finger protein 43; Dvl: disheveled; AP2: adapter protein 2; APC: adenomatous polyposis coli; CK1α: casein kinase 1α; GSK3: glycogen synthase kinase 3; Gro/TLE: groucho/transducin-like enhancer of split proteins; Pygo: pygopus; BCL9: B cell lymphoma 9 protein; Ebd1: earthbound 1; RSPO: R-spondin family of secreted ligands; LGR: leucine-rich repeat-containing G-protein coupled receptors; HSPG: heparan sulfate proteoglycans; SIAH1: siah E3 ubiquitin ligase 1; PP2A: protein phosphatase 2A.

Figure 2

CK1α splice variants. Human CK1α undergoes alternative splicing to produce four splice variants, as shown. These CK1α splice variants are characterized by the insertion of two polypeptide sequences: a long insertion (L) that contains a nuclear localization signal (NLS) into the protein kinase domain, and a short insertion (S) close to the C-terminus. LS: CK1α with both L and S inserts; S: CK1α with only an S insert; NI: CK1α with no insert; SN: CK1α LS with an N-terminal truncation.

Figure 3

CK1α regulatory subunits. Proteins that have been reported to regulate CK1α are shown. These proteins bind to CK1α and lead to indicated regulatory outcomes of CK1α. GLIPR1: glioma pathogenesis-related protein 1; FAM83G: family with sequence similarity 83G protein; DDX3: DEAD-box RNA helicase 3; MDMX: murine double minute X.

Figure 4

CK1α activators. (A) The structures of two chemically distinct CK1α activators—pyrvinium and SSTC3—and their inactive analogs—VU-WS211 and SSTC111—respectively, are shown. The red boxes highlight key structures needed for maximal efficacy. (B) A model, highlighting how CK1α activators function to increase the catalytic efficiency of CK1α. (C) A model of the mechanism underlying the differential therapeutic index of CK1α activators in normal tissue and Wnt-driven cancer.