期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 281, 期 25, 页码 17156-17163出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M513812200
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资金
- NIAMS NIH HHS [AR49410] Funding Source: Medline
- NIDDK NIH HHS [DK57501] Funding Source: Medline
Genetic evidence from both humans and mice suggests that Wnt/beta-catenin and bone morphogenetic protein (BMP) signaling pathways are essential for bone marrow mesenchymal stem cells to differentiate into osteoblasts. Here we describe a mechanism through which BMPs antagonize Wnt signaling and retard bone marrow mesenchymal stem cell proliferation. Treatment with Wnt3a, but not BMP-2, stimulated Lef1-mediated transcriptional activity, whereas co-stimulation with both Wnt3a and BMP-2 markedly reduced Wnt3a-induced reporter activity. Immunoprecipitation assays in 293T cells transfected with individual Smads and Wnt pathway components revealed a specific interaction between Dvl-1 and Smad1 that was dependent on the presence of Wnt3a or BMP-2. Under unstimulated conditions, Dvl-1 and Smad1 are co-immunoprecipitated and form a complex through the linker region of Smad1. Wnt3a treatment transiently disrupted the Dvl-1/Smad1 interaction coincident with nuclear accumulation of beta-catenin. In contrast, when cells were exposed to both Wnt3a and BMP-2, there was an enhanced accumulation of the Dvl-1-Smad1 complex and a decreased nuclear accumulation of beta-catenin. Expression of a mutant Smad1 protein, which cannot be phosphorylated in response to BMP, eliminated the inhibitory effect of BMP on Wnt-induced beta-catenin accumulation and transcriptional activity. These results identify a potential mechanism whereby BMP-2 antagonizes Wnt signaling in osteoblast progenitors by promoting an interaction between Smad1 and Dvl-1 that restricts beta-catenin activation.
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