Wnt signaling inhibits casein kinase 1α activity by modulating its interaction with protein phosphatase 2A
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.
Authors
- Carolina Cywiak (ORCID: https://orcid.org/0000-0002-5716-0051)
- Chen Shen (ORCID: https://orcid.org/0000-0002-7119-8443)
- Brent T. Harris (ORCID: https://orcid.org/0000-0002-9746-4906)
- Melanie H. Cobb (ORCID: https://orcid.org/0000-0003-0833-5473)
- Yashi Ahmed (ORCID: https://orcid.org/0000-0002-7472-6010)
- Nawat Bunnag (ORCID: https://orcid.org/0000-0002-2594-0459)
- Thomas Rohwetter
- Siva Bharath Merugu (ORCID: https://orcid.org/0000-0003-1750-3256)
- Said M. Afify (ORCID: https://orcid.org/0000-0003-4026-1400)
- Hsin‐Yao Tang (ORCID: https://orcid.org/0000-0003-1838-018X)
- Aradhana Bharti
- Chukwuemeka Ihemelandu
- Christopher Albanese
- Arminja N. Kettenbach (ORCID: https://orcid.org/0000-0003-3979-4576)
- Anmada Nayak (ORCID: https://orcid.org/0000-0003-1275-0899)
- David J. Robbins (ORCID: https://orcid.org/0000-0003-0190-2973)
- Ethan Lee (ORCID: https://orcid.org/0000-0001-8405-6156)
- Daniel T. Wynn (ORCID: https://orcid.org/0000-0001-7447-4346)
- Fan Yang (ORCID: https://orcid.org/0000-0003-3730-8503)
- Wenhui Lu (ORCID: https://orcid.org/0009-0002-2674-4254)
- Lauren Schnitkey
Institutions
- The Wistar Institute (US)
- Dartmouth College (US)
- Georgetown University (US)
- Vanderbilt University (US)
- Georgetown University Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115274
- Citations
- 4
- Primary Topic
- Wnt/β-catenin signaling in development and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Foundation for the National Institutes of Health