The Casein kinase 1α agonist pyrvinium attenuates Wnt-mediated CK1α degradation via interaction with the E3 ubiquitin ligase component Cereblon.

Autor:	Shen C; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA., Nayak A; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA., Neitzel LR; Department of Medicine, University of Maryland, Baltimore, Maryland, USA., Yang F; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA., Li B; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA., Williams CH; Department of Medicine, University of Maryland, Baltimore, Maryland, USA., Hong CC; Department of Medicine, University of Maryland, Baltimore, Maryland, USA., Ahmed Y; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA., Lee E; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA., Robbins DJ; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA. Electronic address: dr956@georgetown.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Aug; Vol. 298 (8), pp. 102227. Date of Electronic Publication: 2022 Jul 01.
DOI:	10.1016/j.jbc.2022.102227
Abstrakt:	The Cullin-RING ligase 4 E3 ubiquitin ligase component Cereblon (CRBN) is a well-established target for a class of small molecules termed immunomodulatory drugs (IMiDs). These drugs drive CRBN to modulate the degradation of a number of neosubstrates required for the growth of multiple cancers. Whereas the mechanism underlying the activation of CRBN by IMiDs is well described, the normal physiological regulation of CRBN is poorly understood. We recently showed that CRBN is activated following exposure to Wnt ligands and subsequently mediates the degradation of a subset of physiological substrates. Among the Wnt-dependent substrates of CRBN is Casein kinase 1α (CK1α), a known negative regulator of Wnt signaling. Wnt-mediated degradation of CK1α occurs via its association with CRBN at a known IMiD binding pocket. Herein, we demonstrate that a small-molecule CK1α agonist, pyrvinium, directly prevents the Wnt-dependent interaction of CRBN with CK1α, attenuating the consequent CK1α degradation. We further show that pyrvinium disrupts the ability of CRBN to interact with CK1α at the IMiD binding pocket within the CRBN-CK1α complex. Of note, this function of pyrvinium is independent of its previously reported ability to enhance CK1α kinase activity. Furthermore, we also demonstrate that pyrvinium attenuates CRBN-induced Wnt pathway activation in vivo. Collectively, these results reveal a novel dual mechanism through which pyrvinium inhibits Wnt signaling by both attenuating the CRBN-mediated destabilization of CK1α and activating CK1α kinase activity. Competing Interests: Conflict of interest D. J. R. and E. L. are founders of StemSynergy Therapeutics, Inc, a company commercializing small-molecule signaling inhibitors, including Wnt inhibitors. All other authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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