Regulation of beta-catenin signaling and maintenance of chondrocyte differentiation by ubiquitin-independent proteasomal degradation of alpha-catenin.
Accumulation of beta-catenin and subsequent stimulation of beta-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 alpha-catenin degradation, the role of alpha-catenin in beta-catenin signaling, and the physiological significance of alpha-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.
Hwang
Sang-Gu
SG
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
Yu
Sung-Sook
SS
Ryu
Je-Hwang
JH
Jeon
Hong-Bae
HB
Yoo
Yung-Joon
YJ
Eom
Soo-Hyun
SH
Chun
Jang-Soo
JS
D000818:Animals; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000166:cytology*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D051153:Wnt Proteins; D051178:alpha Catenin; D051176:beta Catenin
D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D025801:Ubiquitin; D051153:Wnt Proteins; D051178:alpha Catenin; D051176:beta Catenin; D003094:Collagen; D008156:Luciferases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease