Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α
Curtis A. ThorneAlison HansonJudsen SchneiderEmilios TahinciDarren OrtonChristopher S. CselenyiKristin K. JerniganKelly C. MeyersBrian HangAlex G. WatersonKwang‐Ho KimBruce J. MelanconVictor P. GhiduGary A. SulikowskiBonnie LaFleurAdrian SalicLaura A. LeeDavid M. MillerEthan Lee
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Adenomatous polyposis coli
Wnt signaling has been identified as one of the key signaling pathways in cancer, regulating cell growth, motility and differentiation. Because of its widespread activation in diverse human tumor diseases, the Wnt pathway has gained considerable and growing interest in tumor research over recent years. Evidence that altered Wnt signaling is important for human tumor development came from three major findings: (i) the tumor suppressor adenomatous polyposis coli (APC) binds to the Wnt pathway component β-catenin and is involved in its degradation, (ii) mutations of APC in colon tumors lead to stabilization of the β-catenin protein and (iii) tumor-associated mutations of β-catenin in colorectal cancer as well as in other tumor types lead to its stabilisation, qualifying β-catenin as a proto-oncogene. Here we will describe the biochemical interactions which shape the Wnt pathway and focus on its role in tumorigenesis.
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The canonical Wnt pathway is recurrently used during embryogenesis and adult life. To track the cellular output of Wnt signaling in a living organism, we designed a hormone‐inducible Wnt responsive system, capable to dynamically and specifically report Wnt pathway activities through eGFP expression. In contrast to previous in vivo reporters, our system essentially avoids interference of consecutive signals by remaining dormant until addition of hormone, which makes it a valuable tool to map canonical Wnt signaling in post‐embryonic stages. Transgenic Xenopus laevis embryos were analyzed revealing at tadpole stage in specific tissues and organs cell populations with high Wnt pathway activity.
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Abstract Wnt/β-catenin signaling is essential for intestinal homeostasis and is aberrantly activated in most colorectal cancers (CRC) through mutation of the tumor suppressor Adenomatous Polyposis Coli ( APC ). APC is an essential component of a cytoplasmic protein complex that targets β-catenin for destruction. Following Wnt ligand presentation, this complex is inhibited. However, a role for APC in this inhibition has not been shown. Here, we utilized Wnt3a-beads to locally activate Wnt co-receptors. In response, the endogenous β-catenin destruction complex reoriented toward the local Wnt cue in CRC cells with full-length APC, but not if APC was truncated or depleted. Non-transformed human colon epithelial cells displayed similar Wnt-induced destruction complex localization which appeared to be dependent on APC and less so on Axin. Our results expand the current model of Wnt/β-catenin signaling such that in response to Wnt, the β-catenin destruction complex: (1) maintains composition and binding to β-catenin, (2) moves toward the plasma membrane, and (3) requires full-length APC for this relocalization.
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Wnt signaling is essential for intestinal homeostasis and is aberrantly activated in the majority of colorectal cancers (CRC). In over 80% of CRC, the tumor suppressor Adenomatous Polyposis Coli (APC) is mutated, resulting in expression of a truncated protein product. APC is a key component of the β‐catenin destruction complex, which maintains low cellular levels of β‐catenin but is inhibited following Wnt ligand presentation. The precise mechanism underlying β‐catenin destruction complex inhibition is not clear, nor is the exact role of APC in the complex. APC is primarily considered a core component of the destruction complex but has been shown to have other roles involving β‐catenin nuclear import/export and cytoskeletal functions. Here, we use Wnt3a beads to study the response of endogenous Wnt components to a local Wnt cue. Using three CRC cell lines, each with a different Wnt pathway status, we demonstrate that localized Wnt redistributes pathway components toward the Wnt source in the presence of full‐length, but not truncated APC. Further, use of the Wnt3a‐beads to perform protein pull‐down demonstrates that APC and β‐catenin both associate with the Wnt‐beads. APC depletion in nontransformed human colon epithelial cells diminishes this Wnt‐induced redistribution. Our results suggest revision of the current model as follows. In response to Wnt, the β‐catenin destruction complex: 1) maintains composition and binding to β‐catenin, 2) translocates to the plasma membrane, and 3) requires full‐length APC for this membrane trafficking. Currently, work is being performed to uncover mechanistic insights into the role of APC in destruction complex reorientation to a Wnt3a signal. Support or Funding Information This study was supported by the National Science Foundation [grant number IOS‐1456538] and by the National Institutes of Health [P30CA168524].
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Keiji Itoh and Sergei Y. Sokol Department of Microbiology and Molecular Genetics, Harvard Medical School and Molecular Medicine Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215 USA
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Activation of the Wnt signaling pathway via mutation of the adenomatous polyposis coli gene (APC) is a critical event in the development of colon cancer.For colon carcinogenesis, however, constitutive signaling through the canonical Wnt pathway is not a singular event.Here we review how canonical Wnt signaling is modulated by intracellular LEF/TCF composition and location, the action of different Wnt ligands, and the secretion of Wnt inhibitory molecules.We also review the contributions of non-canonical Wnt signaling and other distinct pathways in the tumor micro environment that cross-talk to the canonical Wnt pathway and thereby influence colon cancer progression.These 'non-APC' aspects of Wnt signaling are considered in relation to the development of potential agents for the treatment of patients with colon cancer.Regulatory pathways that influence Wnt signaling highlight how it might be possible to design therapies that target a network of signals beyond that of APC and β-catenin.
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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.
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