Targeting of TAK1 in inflammatory disorders and cancer

Sakurai, Hiroaki

doi:10.1016/j.tips.2012.06.007

Cited by 320 publications

(296 citation statements)

References 93 publications

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“…When activated, TAK1 mediates phosphorylation of IKK in association with its activator proteins TAB1 and TAB2 or the structurally related TAB3 (15). Among these activator proteins, TAB1 has been recognized to be sufficient for the association with and the induction of the catalytic activity of TAK1 (25) and also prevention of its dephosphorylation and inactivation (26).…”

Section: Minocycline Suppresses Tgf-b-activated Kinase 1 Activation Amentioning

confidence: 99%

“…IKK complex is activated either through autophosphorylation or via phosphorylation by a series of mitogenactivated kinase kinase kinases (MAP3K) including TGFb-activated kinase-1 (TAK1). TAK1 has emerged as the most central IKK kinase (14), which gets activated in conjunction with its activator proteins, TAK1-binding protein (TAB)-1, TAB2, and TAB3 in response to divergent stimuli such as lipopolysaccharides, IL-1b, TNF-a, and TGF-b (15).…”

Section: Introductionmentioning

confidence: 99%

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RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Ataie-Kachoie

Badar

Morris

et al. 2013

Molecular Cancer Research

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Substantial evidence supports the critical role of NF-kB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-kB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-kB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-kB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IkBa kinase (IKK) activation, IkBa phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-b-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-b and TAK1. Further studies demonstrated that minocycline downregulated TGF-b1 expression. Enforced TGF-b1 expression induced NF-kB activity, and minocycline rescued this effect. Consistent with this finding, TGF-b1 knockdown suppressed NF-kB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-kB activity is mediated, in part, through inhibition of TGF-b1. Furthermore, the influence of minocycline on NF-kB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-kB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-b-NF-kB axis in ovarian cancer.

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Section: Minocycline Suppresses Tgf-b-activated Kinase 1 Activation Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Ataie-Kachoie

Badar

Morris

et al. 2013

Molecular Cancer Research

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“…4 Since this original finding, TAK1 also has been shown to be activated by a number of signaling molecules including cytokines such as TNFa and IL-1; ligands that interact with Toll-like receptors, B-cell receptor and T-cell receptor; and the lipotoxic molecule, ceramide. [5][6][7][8][9][10][11][12][13] Other endogenous death ligands of the TNF family, including TRAIL, also induce TAK1 activation. 14,15 Exogenous stressors and environmental changes such as osmotic stress, UV irradiation, ischemia and nutrient withdrawal activate TAK1.…”

Section: Tak1 Activation and Downstream Pathwaysmentioning

confidence: 99%

“…TAK1-NF-kB pathway: TAK1 is a well-documented upstream kinase of NF-kB. 3,6,7 NF-kB transcriptionally upregulates antiapoptotic protein such as c-FLIP and IAP family proteins ( Figure 1). The IAP family includes cIAP1, cIAP2 and XIAP, which can inhibit caspase activation.…”

Section: Tak1 Inhibits Apoptosismentioning

confidence: 99%

TAK1 control of cell death

2014

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Programmed cell death, a physiologic process for removing cells, is critically important in normal development and for elimination of damaged cells. Conversely, unattended cell death contributes to a variety of human disease pathogenesis. Thus, precise understanding of molecular mechanisms underlying control of cell death is important and relevant to public health. Recent studies emphasize that transforming growth factor-b-activated kinase 1 (TAK1) is a central regulator of cell death and is activated through a diverse set of intra-and extracellular stimuli. The physiologic importance of TAK1 and TAK1-binding proteins in cell survival and death has been demonstrated using a number of genetically engineered mice. These studies uncover an indispensable role of TAK1 and its binding proteins for maintenance of cell viability and tissue homeostasis in a variety of organs. TAK1 is known to control cell viability and inflammation through activating downstream effectors such as NF-jB and mitogen-activated protein kinases (MAPKs). It is also emerging that TAK1 regulates cell survival not solely through NF-jB but also through NF-jB-independent pathways such as oxidative stress and receptor-interacting protein kinase 1 (RIPK1) kinase activity-dependent pathway. Moreover, recent studies have identified TAK1's seemingly paradoxical role to induce programmed necrosis, also referred to as necroptosis. This review summarizes the consequences of TAK1 deficiency in different cell and tissue types from the perspective of cell death and also focuses on the mechanism by which TAK1 complex inhibits or promotes programmed cell death. This review serves to synthesize our current understanding of TAK1 in cell survival and death to identify promising directions for future research and TAK1's potential relevance to human disease pathogenesis.

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“…Tak1 activation was shown to be regulated by ubiquitination of lysine residues within Tak1 (20)(21)(22)(23)(24). Because we reported earlier that Itch targets Tak1 for ubiquitination (14), we sought to get molecular insights into Tak1 ubiquitination by a proteomics approach using mass spectrometry.…”

Section: Resultsmentioning

confidence: 99%

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

Kathania

Zeng

Yadav

et al. 2015

The Journal of Immunology

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The ubiquitin-ligating enzyme (E3) Itch plays a crucial role in the regulation of inflammation, and Itch deficiency leads to severe airway inflammation. However, the molecular mechanisms by which Itch function is regulated remain elusive. In this study, we found that nontypeable Haemophilus influenzae induces the association of Itch with Ndfip1. Both Itch−/− and Ndfip1−/− mice exhibited severe airway inflammation in response to nontypeable Haemophilus influenza, which was associated with elevated expression of proinflammatory cytokines. Ndfip1 enhanced Itch ligase activity and facilitated Itch-mediated Tak1 ubiquitination. Mechanistically, Ndfip1 facilitated recruitment of ubiquitin-conjugating enzyme (E2) UbcH7 to Itch. The N-terminal region of Ndfip1 binds to UbcH7, whereas the PY motif binds to Itch. Hence, Ndfip1 acts as an adaptor for UbcH7 and Itch. Reconstitution of full-length Ndfip1 but not the mutants that fail to interact with either UbcH7 or Itch, restored the defect in Tak1 ubiquitination and inhibited elevated proinflammatory cytokine expression by Ndfip1−/− cells. These results provide new mechanistic insights into how Itch function is regulated during inflammatory signaling, which could be exploited therapeutically in inflammatory diseases.

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Targeting of TAK1 in inflammatory disorders and cancer

Cited by 320 publications

References 93 publications

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

TAK1 control of cell death

Ndfip1 Regulates Itch Ligase Activity and Airway Inflammation via UbcH7

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