Structural coupling of Smad and Runx2 for execution of the BMP2 osteogenic signal
Authors
Javed, AmjadBae, Jong-Sup
Afzal, Faiza
Gutierrez, Soraya E.
Pratap, Jitesh
Zaidi, Sayyed K.
Lou, Yang
Van Wijnen, Andre J.
Stein, Janet L.
Stein, Gary S.
Lian, Jane B.
UMass Chan Affiliations
Department of Cell Biology and Cancer CenterDocument Type
Journal ArticlePublication Date
2008-01-22Keywords
Amino Acid Sequence; Animals; Biological Markers; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cell Differentiation; Core Binding Factor Alpha 1; Subunit; Hela Cells; Humans; Mice; Mice, Knockout; Molecular Sequence Data; Mutation; Osteoblasts; *Osteogenesis; Phenotype; Protein Binding; *Signal Transduction; Smad Proteins; Transforming Growth Factor betaLife Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Two regulatory pathways, bone morphogenetic protein (BMP)/transforming growth factor-beta (TGFbeta) and the transcription factor RUNX2, are required for bone formation in vivo. Here we show the interdependent requirement of these pathways to induce an osteogenic program. A panel of Runx2 deletion and point mutants was used to examine RUNX2-SMAD protein-protein interaction and the biological consequences on BMP2-induced osteogenic signaling determined in Runx2 null cells. These cells do not respond to BMP2 signal in the absence of Runx2. We established that a triple mutation in the C-terminal domain of RUNX2, HTY (426-428), disrupts the RUNX2-SMAD interaction, is deficient in its ability to integrate the BMP2/TGFbeta signal on promoter reporter assays, and is only marginally functional in promoting early stages of osteoblast differentiation. Furthermore, the HTY mutation overlaps the unique nuclear matrix targeting signal of Runx factors and exhibits reduced subnuclear targeting. Thus, formation of a RUNX2-SMAD osteogenic complex and subnuclear targeting are structurally and functionally inseparable. Our results establish the critical residues of RUNX2 for execution and completion of BMP2 signaling for osteoblastogenesis through a mechanism that requires RUNX2-SMAD transcriptional activity.Source
J Biol Chem. 2008 Mar 28;283(13):8412-22. Epub 2008 Jan 18. Link to article on publisher's siteDOI
10.1074/jbc.M705578200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32879PubMed ID
18204048Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M705578200