Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix.
E3 ubiquitin ligase Cbl-b and c-Cbl play important roles in bone formation and maintenance. Cbl-b and c-Cbl regulate the activity of various receptor tyrosine kinases and intracellular protein tyrosine kinases mainly by regulating the degradation of target proteins. However, the precise mechanisms of how Cbl-b and c-Cbl regulate osteoblast differentiation are not well known. In this study, we investigated potential targets of Cbl-b and c-Cbl. We found that Cbl-b and c-Cbl inhibit BMP2-induced osteoblast differentiation in mesenchymal cells. Among various osteogenic transcription factors, we identified that Cbl-b and c-Cbl suppress the protein stability and transcriptional activity of Osterix. Our results suggest that Cbl-b and c-Cbl inhibit the function of Osterix by enhancing the ubiquitin-proteasome-mediated degradation of Osterix. Taken together, we propose novel regulatory roles of Cbl-b and c-Cbl during osteoblast differentiation in which Cbl-b and c-Cbl regulate the degradation of Osterix through the ubiquitin-proteasome pathway.
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
You Hee
YH
Choi
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
Younho
Y
Han
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
Sung Ho
SH
Lee
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
Yun-Hye
YH
Jin
Department of Life Science and Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
Minjin
M
Bahn
Department of Life Science and Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
Kyu Chung
KC
Hur
Department of Life Science and Global Top5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: cyeo@ewha.ac.kr.
Chang-Yeol
CY
Yeo
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: kwanglee@chonnam.ac.kr.
Kwang Youl
KY
Lee
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D050721:Proto-Oncogene Proteins c-cbl
Cbl; Osteoblast differentiation; Osterix; Ubiquitination