Hui-Yi Kua,
Huijuan Liu,
Wai Fook Leong,
Lili Li,
Deyong Jia,
Gang Ma,
Yuanyu Hu,
Xueying Wang,
Jenny F L Chau,
Ye-Guang Chen,
Yuji Mishina,
Sharon Boast,
James Yeh,
Li Xia,
Guo-Qiang Chen,
Lin He, Stephen P Goff,
Baojie Li
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ABSTRACT: 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.
Nature Cell Biology 06/2012; 14(7):727-37. · 19.49 Impact Factor
