Regulation of beta-catenin signaling and maintenance of chondrocyte differentiation by ubiquitin-independent proteasomal degradation of alpha-catenin

Abstract

Accumulation of beta-catenin and subsequent stimulation of beta-catenin-T cell-factor (Tcf)/lymphoid-enhancer-factor (Lef) transcriptional activity causes dedifferentiation of articular chondrocytes, which is characterized by decreased type II collagen expression and initiation of type I collagen expression. This study examined the mechanisms of alpha-catenin degradation, the role of alpha-catenin in beta-catenin signaling, and the physiological significance of beta-catenin regulation of beta-catenin signaling in articular chondrocytes. We found that both alpha- and beta-catenin accumulated during dedifferentiation of chondrocytes by escaping from proteasomal degradation. beta-Catenin degradation was ubiquitination-dependent, whereas alpha-catenin was proteasomally degraded in a ubiquitination-independent fashion. The accumulated alpha- and beta-catenin existed as complexes in the cytosol and nucleus. The complex formation between alpha- and beta-catenin blocked proteasomal degradation of alpha-catenin and also inhibited beta-catenin- Tcf/Lef transcriptional activity and the suppression of type II collagen expression associated with ectopic expression of beta-catenin, the inhibition of proteasome, or Wnt signaling. Collectively, our results indicate that ubiquitin-independent degradation of alpha-catenin regulates beta-catenin signaling and maintenance of the differentiated phenotype of articular chondrocytes.