Transforming Growth Factor-β-activated Kinase-1 (TAK1), a MAP3K, Interacts with Smad Proteins and Interferes with Osteogenesis in Murine Mesenchymal Progenitors

Abstract

TAK1 (transforming growth factor-␤-activated kinase-1), a MAP3K with considerable sequence similarity to Raf-1 and MEKK-1, has been identified as a transforming growth factor-␤/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 RSmad 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 finetuning of BMP effects during osteogenic development.

Transforming Growth Factor-β (TGF-β1) Activates TAK1 via TAB1-mediated Autophosphorylation, Independent of TGF-β Receptor Kinase Activity in Mesangial Cells

“…FLAG-tagged wild type TAK1 (FLAG-TAK1), kinase-deficient mutant TAK1 (FLAG-TAK1-KD (K63W)), and C-terminal-truncated mutant TAK1 (FLAG-TAK1⌬C) were kindly provided by G. Gross (42). To amplify respective cDNAs, various PCR primer sets were synthesized according to corresponding DNA sequences (mouse TAK1, BC006665; rat T␤RI; NM_012775).…”

“…These data implicate a crucial role of TAK1 in extracellular matrix production and tissue fibrosis. TAK1 is also implicated in regulation of cell cycle (38), cell apoptosis (39 -41), and the Smad signaling pathway (42)(43)(44). Thus, TAK1 may function as an important regulator and mediator of TGF-␤1-induced Smad-dependent and Smad-independent signaling pathways.…”

TAK1, more than just innate immunity

“…The identification of direct interaction between the mad homology 2 domain (MH2) of Smads and TAK1 indicates crosstalk between TGF-b-activated Smad and TAK1 pathways (51,52). In some studies, TAK1 is required along with the Smads for optimal activation of TGF-b target genes through activating transcription factor 2 (ATF2) (39).…”

In vivo RNAi-mediated silencing of TAK1 decreases inflammatory Th1 and Th17 cells through targeting of myeloid cells

“…2 As a key regulator of the TGF/BMP downstream signaling pathways, TAK1 acts in a number of physiologic processes where it is involved in the control of morphogenesis and tissue homeostasis. [3][4][5][6][7][8] In addition, TAK1 plays a critical role in innate and adaptive immune responses and in inflammation by integrating signaling pathways downstream of interleukin-1 (IL-1), IL-17, IL-18, tumor necrosis factor (TNF)-␣, Toll-like receptor (TLR), and NOD-like receptor, as well as the receptor activator of nuclear factor (NF)-B ligand (RANKL). 2,6,[9][10][11][12][13][14][15] TAK1 deficiency in mice results in embryonic lethality, and therefore, conditional knockout systems have been used to reveal additional in vivo roles of TAK1 in T-and B-cell differentiation and activation.…”