Shen C, Nayak A, Neitzel LR, Yang F, Li B, Williams CH, Hong CC, Ahmed Y, Lee E, Robbins DJ

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 ...

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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 1? (CK1?), a known negative regulator of Wnt signaling. Wnt-mediated degradation of CK1? occurs via its association with CRBN at a known IMiD binding pocket. Herein, we demonstrate that a small-molecule CK1? agonist, pyrvinium, directly prevents the Wnt-dependent interaction of CRBN with CK1?, attenuating the consequent CK1? degradation. We further show that pyrvinium disrupts the ability of CRBN to interact with CK1? at the IMiD binding pocket within the CRBN-CK1? complex. Of note, this function of pyrvinium is independent of its previously reported ability to enhance CK1? 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 CK1? and activating CK1? kinase activity.

Date: Dec. 01, 2021

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