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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Sequence
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Animals
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Bone Morphogenetic Protein Receptors, Type I / genetics
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Bone Morphogenetic Protein Receptors, Type I / metabolism
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Bone Morphogenetic Protein Receptors, Type II / metabolism
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Bone Morphogenetic Proteins / metabolism*
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Cell Proliferation*
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Cells, Cultured
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Cellular Senescence*
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Cyclin-Dependent Kinase Inhibitor p16 / deficiency
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
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Enzyme Activation
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Genotype
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Inhibitor of Differentiation Protein 1 / metabolism
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MAP Kinase Kinase Kinases / metabolism
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Mesenchymal Stem Cells / enzymology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Molecular Sequence Data
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Osteoblasts / enzymology*
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Phenotype
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Phosphorylation
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism*
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Signal Transduction
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Smad1 Protein / metabolism
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Smad5 Protein / metabolism
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Smad8 Protein / metabolism
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Time Factors
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Transfection
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Bone Morphogenetic Proteins
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Cdkn2a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Idb1 protein, mouse
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Inhibitor of Differentiation Protein 1
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Smad1 Protein
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Smad1 protein, mouse
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Smad5 Protein
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Smad5 protein, mouse
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Smad8 Protein
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Smad9 protein, mouse
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Tab1 protein, mouse
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-abl
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Mapk1 protein, mouse
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Bmpr1a protein, mouse
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Bmpr2 protein, mouse
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Bone Morphogenetic Protein Receptors, Type I
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Bone Morphogenetic Protein Receptors, Type II