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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: David J. Robbins  

PROVIDER: MSV000095904 | MassIVE |

SECONDARY ACCESSION(S): PXD056028

REPOSITORIES: MassIVE