Casein Kinase 1α as a Regulator of Wnt-Driven Cancer.
CK1α
Wnt
cancer
kinase agonists
review
targeted therapies
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
18 Aug 2020
18 Aug 2020
Historique:
received:
24
07
2020
revised:
10
08
2020
accepted:
14
08
2020
entrez:
23
8
2020
pubmed:
23
8
2020
medline:
17
2
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32824859
pii: ijms21165940
doi: 10.3390/ijms21165940
pmc: PMC7460588
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Activators
0
Casein Kinase Ialpha
EC 2.7.11.1
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM122222
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK058404
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122516
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM121421
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA219189
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM136233
Pays : United States
Organisme : NIH HHS
ID : R01CA219189, R01NS110591, R35GM122516, R01GM121421, R01GM122222, R35GM136233, R01CA244188, P30CA240139
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244188
Pays : United States
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