Transforming growth factor-beta-activated kinase-1 (TAK1), a MAP3K, interacts with Smad proteins and interferes with osteogenesis in murine mesenchymal progenitors.
TAK1 (transforming growth factor-beta-activated kinase-1), a MAP3K with considerable sequence similarity to Raf-1 and MEKK-1, has been identified as a transforming growth factor-beta/bone morphogenetic protein (BMP)-activated cytosolic component of the MAPK pathways. In this investigation, the molecular interactions between TAK1 and Smad proteins were characterized as well as their influence on BMP-mediated mesenchymal cell differentiation along the osteogenic/chondrogenic pathway. In co-immunoprecipitations we found an interaction of TAK1 with all Smads tested, R-Smads Smads1-5, the co-Smad Smad4, and the inhibitory Smads (I-Smad6 and I-Smad7). Smad interaction with TAK1 takes place through their MH2 domain. This interaction is dependent on the presence of an active kinase domain in TAK1. TAK1 dramatically interferes with R-Smad transactivation in reporter assays and affects subcellular distribution of Smad proteins. Activated TAK1 also interferes with BMP-dependent osteogenic development in murine mesenchymal progenitor cells (C3H10T 1/2). A potential TAK1-mediated apoptosis process could be excluded for these cells. Both synergistic and interfering influences of TAK1 on BMP-mediated Smad-signaling have been reported previously. We suggest that TAK1 is a factor that is involved in the fine-tuning of BMP effects during osteogenic development.
Hoffmann
Andrea
A
Gesellschaft für Biotechnologische Forschung, "Signal Transduction and Gene Regulation," Mascheroder Weg 1, 38124 Braunschweig, Germany.
Preobrazhenska
Olena
O
Wodarczyk
Claas
C
Medler
Yvonne
Y
Winkel
Andreas
A
Shahab
Sandra
S
Huylebroeck
Danny
D
Gross
Gerhard
G
Verschueren
Kristin
K
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D026481:Blotting, Far-Western; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism* / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010012:Osteogenesis; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D000099151:MAP Kinase Kinase Kinase 7
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D020930:MAP Kinase Kinase Kinases; D051785:Smad Proteins; D015534:Trans-Activators; D000099151:MAP Kinase Kinase Kinase 7