Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A

• Published in: Cell reports (Cambridge) Vol. 44; no. 2; p. 115274
• Main Authors: Shen, Chen, Lu, Wenhui, Merugu, Siva B., Bharti, Aradhana, Afify, Said M., Schnitkey, Lauren, Wynn, Daniel T., Yang, Fan, Rohwetter, Thomas M., Nayak, Anmada, Bunnag, Nawat, Cywiak, Carolina, Tang, Hsin-Yao, Harris, Brent T., Albanese, Christopher, Ihemelandu, Chukwuemeka, Cobb, Melanie H., Kettenbach, Arminja, Lee, Ethan, Ahmed, Yashi, Robbins, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.02.2025; Elsevier
• Subjects: autophosphorylation; Axin Protein - metabolism; beta Catenin - metabolism; Casein Kinase Ialpha - metabolism; Cell Line, Tumor; CK1α; colorectal cancer; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; CP: Cancer; CP: Molecular biology; HEK293 Cells; Humans; Phosphorylation; Protein Binding; Protein Phosphatase 2 - metabolism; protein phosphatase 2A; Wnt signaling; Wnt Signaling Pathway; Wnt signaling; colorectal cancer; autophosphorylation; protein phosphatase 2A; CP: Cancer; CK1α; CP: Molecular biology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2025.115274

The mechanism by which Wnt signaling, an essential pathway controlling development and disease, stabilizes β-catenin has been a subject of debate over the last four decades. Casein kinase 1α (CK1α) functions as a pivotal negative regulator of this signaling pathway, initiating the events that destabilize β-catenin. However, whether and how CK1α activity is regulated in Wnt-off and Wnt-on states remains poorly understood. We now show that CK1α activity requires its association with the α catalytic subunit of protein phosphatase 2A (PPP2CA) on AXIN, the scaffold protein of the β-catenin destruction complex. Wnt stimulation induces the dissociation of PPP2CA from CK1α, resulting in CK1α autophosphorylation and its consequent inactivation. Moreover, autophosphorylated CK1α is enriched in a subset of colorectal cancers (CRCs) harboring constitutive Wnt activation. Our findings identify a mechanism by which Wnt stimulation inactivates CK1α, filling a critical gap in our understanding of Wnt signaling, with relevance for CRC. [Display omitted] •Wnt signaling induces CK1α autophosphorylation, which inhibits CK1α activity•Wnt signaling regulates the dynamics of CK1α/PP2A/AXIN complex, causing CK1α autoinhibition•Autophosphorylated CK1α is enriched in a subset of Wnt-dependent colorectal cancers Shen et al. show that the activity of a ubiquitous enzyme, CK1α, is autoinhibited upon the stimulation of Wnt signaling. The underlying mechanism involves the rearrangement of a multiprotein complex consisting of CK1α, PP2A, and AXIN. The authors further illustrate the importance of CK1α autoinhibition in colorectal cancer growth.