A dishevelled-1/Smad1 interaction couples WNT and bone morphogenetic protein signaling pathways in uncommitted bone marrow stromal cells.
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-inducedbeta-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.
Liu
Zhongyu
Z
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019.
Tang
Yi
Y
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019.
Qiu
Tao
T
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019.
Cao
Xu
X
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019.
Clemens
Thomas L
TL
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019. Electronic address: tclemens@path.uab.edu.
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D000072261:Dishevelled Proteins; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000502:physiology*; D015398:Signal Transduction; D051898:Smad1 Protein / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D048868:Adaptor Proteins, Signal Transducing; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; D010750:Phosphoproteins; C497399:SMAD1 protein, human; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D016212:Transforming Growth Factor beta; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse