Centrosomes are required for proper β-catenin processing and Wnt response

Mol Biol Cell. 2020 Aug 1;31(17):1951-1961. doi: 10.1091/mbc.E20-02-0139. Epub 2020 Jun 17.

Abstract

The Wnt/β-catenin signaling pathway is central to metazoan development and routinely dysregulated in cancer. Wnt/β-catenin signaling initiates transcriptional reprogramming upon stabilization of the transcription factor β-catenin, which is otherwise posttranslationally processed by a destruction complex and degraded by the proteasome. Since various Wnt signaling components are enriched at centrosomes, we examined the functional contribution of centrosomes to Wnt signaling, β-catenin regulation, and posttranslational modifications. In HEK293 cells depleted of centrosomes we find that β-catenin synthesis and degradation rates are unaffected but that the normal accumulation of β-catenin in response to Wnt signaling is attenuated. This is due to accumulation of a novel high-molecular-weight form of phosphorylated β-catenin that is constitutively degraded in the absence of Wnt. Wnt signaling operates by inhibiting the destruction complex and thereby reducing destruction complex-phosphorylated β-catenin, but high-molecular-weight β-catenin is unexpectedly increased by Wnt signaling. Therefore these studies have identified a pool of β-catenin effectively shielded from regulation by Wnt. We present a model whereby centrosomes prevent inappropriate β-catenin modifications that antagonize normal stabilization by Wnt signals.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Centrosome / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Processing, Post-Translational
  • Transcription Factors / metabolism
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, human
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • Proteasome Endopeptidase Complex