Centrosomes are required for proper -catenin processing and Wnt response

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