Journal
NATURE CELL BIOLOGY
Volume 14, Issue 7, Pages 727-737Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2528
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Funding
- Ministry of Science and Technology of China [2012CB966901]
- National Natural Science Foundation of China [81130039, 31071229, 81121001]
- Shanghai Pujiang Program [10PJ1405000]
- Ministry of Education
- Agency for Science, Technology and Research of Singapore
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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 p(16INK4a). c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p(16INK4a) 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.
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