Ethan Lee
Faculty Member
Last active: 8/24/2020

The CK1α Activator Pyrvinium Enhances the Catalytic Efficiency (/) of CK1α.

Shen C, Li B, Astudillo L, Deutscher MP, Cobb MH, Capobianco AJ, Lee E, Robbins DJ
Biochemistry. 2019 58 (51): 5102-5106

PMID: 31820934 · PMCID: PMC6942998 · DOI:10.1021/acs.biochem.9b00891

The serine/threonine protein kinase casein kinase 1α (CK1α) functions as a negative regulator of Wnt signaling, phosphorylating β-catenin at serine 45 (P-S45) to initiate its eventual ubiquitin-mediated degradation. We previously showed that the repurposed, FDA-approved anthelminthic drug pyrvinium potently inhibits Wnt signaling and Moreover, we proposed that pyrvinium's Wnt inhibitory activity was the result of its function as an activator of CK1α. An understanding of the mechanism by which pyrvinium activates CK1α is important because pyrvinium was given an orphan drug designation by the FDA to treat familial adenomatous polyposis, a precancerous condition driven by constitutive Wnt signaling. In the current study, we show that pyrvinium stimulates the phosphorylation of S45 β-catenin, a known CK1α substrate, in a cell-based assay, and does so in a dose- and time-dependent manner. Alternative splicing of CK1α results in four forms of the protein with distinct biological properties. We evaluated these splice products and identified the CK1α splice variant, CK1αS, as the form that exhibits the most robust response to pyrvinium in cells. Kinetic studies indicate that pyrvinium also stimulates the kinase activity of purified, recombinant CK1αS , increasing its catalytic efficiency (/) toward substrates. These studies provide strong and clear mechanistic evidence that pyrvinium enhances CK1α kinase activity.

MeSH Terms (7)

Biocatalysis Casein Kinase Ialpha Enzyme Activation HEK293 Cells Humans Kinetics Pyrvinium Compounds

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