c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression
| Autor: | Baojie Li, Deyong Jia, Guo Qiang Chen, Xueying Wang, Lin He, Stephen P. Goff, Gang Ma, Li Xia, Wai Fook Leong, Yuanyu Hu, Ye-Guang Chen, Lili Li, Jenny Fung Ling Chau, Hui Yi Kua, James Yeh, Yuji Mishina, Sharon Boast, Huijuan Liu |
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| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
Senescence Inhibitor of Differentiation Protein 1 Smad5 Protein Time Factors Genotype Molecular Sequence Data Bone morphogenetic protein Bone Morphogenetic Protein Receptors Type II Transfection Article Smad1 Protein Mice hemic and lymphatic diseases medicine Animals Amino Acid Sequence Phosphorylation Proto-Oncogene Proteins c-abl neoplasms Bone Morphogenetic Protein Receptors Type I Cells Cultured Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 Adaptor Proteins Signal Transducing Cell Proliferation Mice Knockout Mitogen-Activated Protein Kinase 1 ABL Mitogen-Activated Protein Kinase 3 Osteoblasts Chemistry Osteoblast Mesenchymal Stem Cells Cell Biology MAP Kinase Kinase Kinases BMPR1A BMPR2 Cell biology Enzyme Activation Mice Inbred C57BL medicine.anatomical_structure Phenotype Smad8 Protein embryonic structures Bone Morphogenetic Proteins Tumor Suppressor Protein p53 Signal Transduction |
| Zdroj: | Nat Cell Biol |
| ISSN: | 1476-4679 |
| Popis: | Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion. c-Abl interacts with and phosphorylates BMPRIA and the phosphorylation differentially influences the interaction of BMPRIA with BMPRII and the Tab1-Tak1 complex, leading to uneven activation of Smad1/5/8 and Erk1/2, the canonical and non-canonical BMP pathways that direct the expression of p16(INK4a). c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16(INK4a) upregulation and osteoblast senescence. Mouse genetic studies revealed that p16(INK4a) controls mesenchymal stem cell maintenance and osteoblast expansion and mediates the effects of c-Abl deficiency on osteoblast expansion and bone formation. These findings identify c-Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16(INK4a) expression and osteoprogenitor expansion. |
| Databáze: | OpenAIRE |
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