MassIVE MSV000095904

Partial Public PXD056028

Wnt signaling inhibits Casein kinase 1a activity by modulating its interaction with Protein phosphatase 2A

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Description

The mechanism by which Wnt signaling, an essential pathway controlling development and disease, stabilizes beta-Catenin has been a subject of debate over the last three decades. Casein kinase 1alpha (CK1a) functions as a pivotal negative regulator of this signaling pathway, initiating the events that destabilize beta-Catenin. However, whether and how CK1a activity is regulated in Wnt-off and Wnt-on states remains poorly understood. We now show that CK1a activity requires its association with the alpha catalytic subunit of Protein phosphatase 2A (PPP2CA) on AXIN, the scaffold protein of the beta-Catenin destruction complex. Wnt stimulation induces the dissociation of PPP2CA from CK1a, resulting in CK1a autophosphorylation and its consequent inactivation. Moreover, autophosphorylated CK1a is enriched in a subset of colorectal cancers (CRC) harboring constitutive Wnt activation. Our findings identify a novel mechanism by which Wnt stimulation inactivates CK1a, filling a critical gap in our understanding of Wnt signaling, with relevance for CRC. [doi:10.25345/C58S4K15B] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: CK1a, Wnt signaling, Protein phosphatase 2A, autophosphorylation, colorectal cancer

Contact

Principal Investigators:
(in alphabetical order) 		David J. Robbins, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, United States
Submitting User: tangh

Publications

Shen C, Lu W, Merugu SB, Bharti A, Afify SM, Schnitkey L, Wynn DT, Yang F, Rohwetter TM, Nayak A, Bunnag N, Cywiak C, Tang HY, Harris BT, Albanese C, Ihemelandu C, Cobb MH, Kettenbach A, Lee E, Ahmed Y, Robbins DJ.
Wnt signaling inhibits casein kinase 1? activity by modulating its interaction with protein phosphatase 2A.
Cell Rep. 2025 Feb 25;44(2):115274. Epub 2025 Feb 6.

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