c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression.
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.
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
Hui-Yi
HY
Kua
Huijuan
H
Liu
Wai Fook
WF
Leong
Lili
L
Li
Deyong
D
Jia
Gang
G
Ma
Yuanyu
Y
Hu
Xueying
X
Wang
Jenny F L
JF
Chau
Ye-Guang
YG
Chen
Yuji
Y
Mishina
Sharon
S
Boast
James
J
Yeh
Li
L
Xia
Guo-Qiang
GQ
Chen
Lin
L
He
Stephen P
SP
Goff
Baojie
B
Li
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005838:Genotype; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000201:enzymology*; D010641:Phenotype; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051798:Inhibitor of Differentiation Protein 1; D020930:MAP Kinase Kinase Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016315:Proto-Oncogene Proteins c-abl; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D016159:Tumor Suppressor Protein p53; D000099151:MAP Kinase Kinase Kinase 7; C417743:Cdkn2a protein, mouse; C497455:Idb1 protein, mouse; C497401:Smad1 protein, mouse; C497798:Smad5 protein, mouse; C491621:Smad9 protein, mouse; C531463:Tab1 protein, mouse; C535148:Mapk1 protein, mouse; C498212:Bmpr1a protein, mouse; C498219:Bmpr2 protein, mouse