Regulation of β-Catenin Signaling and Maintenance of Chondrocyte Differentiation by Ubiquitin-independent Proteasomal Degradation of α-Catenin

Abstract

Accumulation of ␤-catenin and subsequent stimulation of ␤-catenin-T cell-factor (Tcf)/lymphoid-enhancerfactor (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 ␣-catenin degradation, the role of ␣-catenin in ␤-catenin signaling, and the physiological significance of ␣-catenin regulation of ␤-catenin signaling in articular chondrocytes. We found that both ␣-and ␤-catenin accumulated during dedifferentiation of chondrocytes by escaping from proteasomal degradation. ␤-Catenin degradation was ubiquitination-dependent, whereas ␣-catenin was proteasomally degraded in a ubiquitination-independent fashion. The accumulated ␣-and ␤-catenin existed as complexes in the cytosol and nucleus. The complex formation between ␣-and ␤-catenin blocked proteasomal degradation of ␣-catenin and also inhibited ␤-catenin-Tcf/Lef transcriptional activity and the suppression of type II collagen expression associated with ectopic expression of ␤-catenin, the inhibition of proteasome, or Wnt signaling. Collectively, our results indicate that ubiquitin-independent degradation of ␣-catenin regulates ␤-catenin signaling and maintenance of the differentiated phenotype of articular chondrocytes.␤-Catenin interacts with cadherin to participate in cell-cell adhesion and regulates gene expression by acting as a transcriptional co-activator (1, 2). In the absence of extracellular stimuli, cytosolic ␤-catenin is phosphorylated by glycogen synthase kinase-3␤, leading to its ubiquitination and subsequent degradation by the 26 S proteasome. However, extracellular stimuli, such as Wnt signaling, lead to the inhibition of glycogen synthase kinase-3␤, escape of ␤-catenin from ubiquitin-dependent proteolytic degradation, and subsequent cytosolic accumulation of ␤-catenin (3). The accumulated ␤-catenin translocates into the nucleus in association with members of the T cell-factor (Tcf) 1 /lymphoid-enhancer-factor (Lef) family of transcription factors, leading to stimulation or suppression of target gene transcription (2). As a transcriptional co-activator, ␤-catenin is involved in the regulation of several biological functions. Our group previously has shown that ␤-catenin regulates maintenance of differentiated phenotypes (4, 5) and expression of cyclooxygenase-2 (6) in chondrocytes by acting as a transcriptional co-activator. We have also shown that Wnt-7a causes dedifferentiation of chondrocytes characterized by suppression of type II collagen expression and the onset of type I collagen expression. Accumulation and stimulation of ␤-catenin transcriptional activity by Wnt-7a signaling is sufficient to cause chondrocyte dedifferentiation (4, 5).␤-Catenin signaling can be regulated by a variety of proteins. Cadherins regulate the transcriptional activity of ␤-catenin in a cell adhesion-independent manner (7, 8) via sequestration of ␤-catenin in the cytoplasm (9), whereas ␥-catenin ...

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