Author:

Keywords:

Active Transport, Cell Nucleus, Animals, Binding Sites, Blotting, Far-Western, Bone Morphogenetic Proteins, Cell Differentiation, Cell Line, DNA-Binding Proteins, Humans, MAP Kinase Kinase Kinases, Mesenchymal Stem Cells, Mice, Osteogenesis, Research Support, Non-U.S. Gov't, Smad Proteins, Trans-Activation (Genetics), Trans-Activators, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, TGF-BETA RECEPTOR, SIGNAL-TRANSDUCTION, P38 MAPK, PATHWAY, DIFFERENTIATION, ACTIVATION, C3H10T1/2, CELLS, EXPRESSION, TARGET, Transcriptional Activation, 03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences, 31 Biological sciences, 32 Biomedical and clinical sciences, 34 Chemical sciences

Abstract:

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.