Transforming Growth Factor -activated Kinase 1 (TAK1) Kinase Adaptor, TAK1-binding Protein 2, Plays Dual Roles in TAK1 Signaling by Recruiting Both an Activator and an Inhibitor of TAK1 Kinase in Tumor Necrosis Factor Signaling Pathway

Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2009; 285(4):2333-9. DOI: 10.1074/jbc.M109.090522
Source: PubMed


Transforming growth factor β-activated kinase 1 (TAK1) kinase is an indispensable signaling intermediate in tumor necrosis
factor (TNF), interleukin 1, and Toll-like receptor signaling pathways. TAK1-binding protein 2 (TAB2) and its closely related
protein, TAB3, are binding partners of TAK1 and have previously been identified as adaptors of TAK1 that recruit TAK1 to a
TNF receptor signaling complex. TAB2 and TAB3 redundantly mediate activation of TAK1. In this study, we investigated the role
of TAB2 by analyzing fibroblasts having targeted deletion of the tab2 gene. In TAB2-deficient fibroblasts, TAK1 was associated with TAB3 and was activated following TNF stimulation. However,
TAB2-deficient fibroblasts displayed a significantly prolonged activation of TAK1 compared with wild type control cells. This
suggests that TAB2 mediates deactivation of TAK1. We found that a TAK1-negative regulator, protein phosphatase 6 (PP6), was
recruited to the TAK1 complex in wild type but not in TAB2-deficient fibroblasts. Furthermore, we demonstrated that both PP6
and TAB2 interacted with the polyubiquitin chains and this interaction mediated the assembly with TAK1. Our results indicate
that TAB2 not only activates TAK1 but also plays an essential role in the deactivation of TAK1 by recruiting PP6 through a
polyubiquitin chain-dependent mechanism.

Full-text preview

Available from:
  • Source
    • "Recently, TAK1 has been characterized as a key regulator in immune and proinflammatory intracellular signaling pathways [2]–[4]. TAK1 can be activated by diverse proinflammatory stimuli, such as tumor necrosis factor-α (TNFα), interleukin-1 (IL-1), bacterial lipopolysaccharide (LPS), and CD40 ligand (CD40L) [2], [5], [6]. The activated TAK1 in turn mediates intracellular signaling, via downstream nuclear factor kappaB (NF-kB), p38 MAPK, and c-Jun N-terminal kinase, which may drive inflammatory and oxidative responses in a cell-type specific manner [2], [3], [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although TAK1 has been implicated in inflammation and oxidative stress, its roles in vascular smooth muscle cells (VSMCs) and in response to vascular injury have not been investigated. The present study aimed to investigate the role of TAK1 in modulating oxidative stress in VSMCs and its involvement in neointima formation after vascular injury. Double immunostaining reveals that vascular injury induces a robust phosphorylation of TAK1 (Thr187) in the medial VSMCs of injured arteries in wildtype mice, but this effect is blocked in CD40-deficient mice. Upregulation of TAK1 in VSMCs is functionally important, as it is critically involved in pro-oxidative and pro-inflammatory effects on VSMCs and eventual neointima formation. In vivo, pharmacological inhibition of TAK1 with 5Z-7-oxozeaenol blocked the injury-induced phosphorylation of both TAK1 (Thr187) and NF-kB/p65 (Ser536), associated with marked inhibition of superoxide production, 3-nitrotyrosine, and MCP-1 in the injured arteries. Cell culture experiments demonstrated that either siRNA knockdown or 5Z-7-oxozeaenol inhibition of TAK1 significantly attenuated NADPH oxidase activation and superoxide production induced by CD40L/CD40 stimulation. Co-immunoprecipitation experiments indicate that blockade of TAK1 disrupted the CD40L-induced complex formation of p22phox with p47phox, p67phox, or Nox4. Blockade of TAK1 also inhibited CD40L-induced NF-kB activation by modulating IKKα/β and NF-kB p65 phosphorylation and this was related to reduced expression of proinflammatory genes (IL-6, MCP-1 and ICAM-1) in VSMCs. Lastly, treatment with 5Z-7-oxozeaenol attenuated neointimal formation in wire-injured femoral arteries. Our findings demonstrate previously uncharacterized roles of TAK1 in vascular oxidative stress and the contribution to neointima formation after vascular injury.
    Full-text · Article · Jul 2014 · PLoS ONE
  • Source
    • "ItisthoughtthatdysregulatedandprolongedTGF-b signalingisimplicatedindiseasestates.Inordertoprevent excessiveactionsofTGF-b1,amechanismforefficientdown- regulationofTAK1activitywouldbeimportant.Ingeneral, tightregulationofintracellularsignalingcascadesisaccomplishedbycyclicphosphorylationanddephosphorylation .In thecaseofTAK1inactivation,severalmembersoftheSer/Thr proteinphosphatasefamilyhavebeendemonstratedtonega- tivelyregulateTAK1activity.PP2Ciscapableofbindingand dephosphorylatingTAK1in293cellsundernonstimulated condition[88] [89].AnotherSer/Thrproteinphosphatase familymember,PP6,interactswithandnegativelyregulates IL-1-inducedTAK1in293cells[90]andTNF-a-inducedTAK1 infibroblasts[91]. WehavereportedthatTAK1activationbyTGF-b1in glomerularmesangialcellsisnegativelyregulatedbyanother Ser/Thrproteinphosphatasefamilymember,PP2A[92], whichwaspreviouslyshowntomediateTGF-binhibitionof p70S6kinase(p70S6K)toinducecell-cycleG1arrest[49]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates a wide variety of cellular functions, including cell growth, cellular differentiation, apoptosis, and wound healing. TGF-β1, the prototype member of the TGF-β superfamily, is well established as a central mediator of renal fibrosis. In chronic kidney disease, dysregulation of expression and activation of TGF-β1 results in the relentless synthesis and accumulation of extracellular matrix proteins that lead to the development of glomerulosclerosis and tubulointerstitial fibrosis, and ultimately to end-stage renal disease. Therefore, specific targeting of the TGF-β signaling pathway is seemingly an attractive molecular therapeutic strategy in chronic kidney disease. Accumulating evidence demonstrates that the multifunctionality of TGF-β1 is connected with the complexity of its cell signaling networks. TGF-β1 signals through the interaction of type I and type II receptors to activate distinct intracellular pathways. Although the Smad signaling pathway is known as a canonical pathway induced by TGF-β1, and has been the focus of many previous reviews, importantly TGF-β1 also induces various Smad-independent signaling pathways. In this review, we describe evidence that supports current insights into the mechanism and function of TGF-β-activated kinase 1 (TAK1), which has emerged as a critical signaling molecule in TGF-β-induced Smad-independent signaling pathways. We also discuss the functional role of TAK1 in mediating the profibrotic effects of TGF-β1.
    Preview · Article · Jun 2012
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell death is an important mechanism to limit uncontrolled T-cell expansion during immune responses. Given the role of death-receptor adapter protein Fas-associated death domain (FADD) in apoptosis, it is intriguing that T-cell receptor (TCR)-induced proliferation is blocked in FADD-defective T cells. Necroptosis is an alternate form of death that can be induced by death receptors and is linked to autophagy. It requires the death domain-containing kinase RIP1 and, in certain instances, RIP3. FADD and its apoptotic partner, Caspase-8, have also been implicated in necroptosis. To accurately assess the role of FADD in mature T-cell proliferation and death, we generated a conditional T-cell-specific FADD knockout mouse strain. The T cells of these mice develop normally, but lack FADD at the mature stage. FADD-deficient T cells respond poorly to TCR triggering, exhibit slow cell cycle entry, and fail to expand over time. We find that programmed necrosis occurs during the late stage of normal T-cell proliferation and that this process is greatly amplified in FADD-deficient T cells. Inhibition of necroptosis using an inhibitor of RIP1 kinase activity rescues the FADD knockout proliferative defect. However, TCR-induced necroptosis did not appear to require autophagy or involve RIP3. Consistent with their defective CD8 T-cell response, these mice succumb to Toxoplasma gondii infection more readily than wild-type mice. We conclude that FADD constitutes a mechanism to keep TCR-induced programmed necrotic signaling in check during early phases of T-cell clonal expansion.
    Full-text · Article · Jul 2010 · Proceedings of the National Academy of Sciences
Show more