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

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 post-translationally 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 post-translational 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.

Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission

“…Building on results demonstrating that β-cat 21 , Axin1 22 and APC 23 localized to the centrosome, we show that all DC components are nucleated by the centrosome into dynamic, liquid-like biomolecular condensates. In support of the molecular crucible theory, we find that nucleation drives efficient degradation of β-cat.…”

Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission

“…Building on results demonstrating that β-cat ( 21 , 22 ), Axin1 ( 23 ), APC ( 24 ), and βTrCP/ Slimb ( 25 ) localize to the centrosome, we show that all DC components are nucleated by the centrosome into liquid-like biomolecular condensates. In support of the molecular crucible theory, we find that nucleation drives efficient degradation of β-cat.…”

Moonlighting at the Poles: Non-Canonical Functions of Centrosomes

“…Nek2 is known to phosphorylate ß -catenin, a multifunctional Wnt-pathway effector implicated in a wide array of biological contexts including centrosome-related cellular processes ( Kaplan et al, 2004 ; Bahmanyar et al, 2008 ; Vora et al, 2020 ). Throughout mitosis, Nek2-mediated ß -catenin phosphorylation prevents its degradation, a mechanism required to maintain high levels of centrosomal ß -catenin ( Mbom et al, 2014 ) and associated with accurate centrosome disjunction.…”