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

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

Summary: 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 th...

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Main Authors: Chen Shen, Wenhui Lu, Siva B. Merugu, Aradhana Bharti, Said M. Afify, Lauren Schnitkey, Daniel T. Wynn, Fan Yang, Thomas M. Rohwetter, Anmada Nayak, Nawat Bunnag, Carolina Cywiak, Hsin-Yao Tang, Brent T. Harris, Christopher Albanese, Chukwuemeka Ihemelandu, Melanie H. Cobb, Arminja Kettenbach, Ethan Lee, Yashi Ahmed, David J. Robbins
Format: Article
Language:English
Published: Elsevier 2025-02-01
Series:Cell Reports
Subjects:
CP: Cancer
CP: Molecular biology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725000452
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Summary:Summary: 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.
ISSN:2211-1247

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