Signaling to NF- B: Regulation by Ubiquitination

Wertz, Ingrid E.; Dixit, Vishva M.

doi:10.1101/cshperspect.a003350

Cited by 269 publications

(250 citation statements)

References 90 publications

(111 reference statements)

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“…Assessing the function of these candidates has shown that components of the NF-κB pathway can serve as vital therapeutic targets for gliomas [32,33]. Several molecular mechanisms for activation of NF-κB signaling have been proposed [1,2,7]. On the other hand, NF-κB signaling has also been found to be restricted by negative feedback mechanisms via induction of NF-κB inhibitors, IκBs and a number of NF-κB-negative regulators, such as A20, CYLD and Cezanne [4,5].…”

Section: Discussionmentioning

confidence: 99%

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miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Song

Lin²,

Gong³

et al. 2012

Cell Res

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Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as important negative regulators that balance the strength and the duration of NF-κB signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancers, which commonly exhibit constitutively activated NF-κB, remains puzzling. Herein, we report that miR-486 directly suppresses NF-κB-negative regulators, CYLD and Cezanne, as well as multiple A20 activity regulators, including ITCH, TNIP-1, TNIP-2 and TNIP-3, resulting in promotion of ubiquitin conjugations in NF-κB signaling and sustained NF-κB activity. Furthermore, we demonstrate that upregulation of miR-486 promotes glioma aggressiveness both in vitro and in vivo through activation of NF-κB signaling pathway. Importantly, miR-486 levels in primary gliomas significantly correlate with NF-κB activation status. These findings uncover a novel mechanism for constitutive NF-κB activation in gliomas and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

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Section: Discussionmentioning

confidence: 99%

“…A growing number of proteins in the NF-κB signal transduction pathway have been identified to be modified by or to interact with ubiquitin. Notably, deregulation of ubiquitin conjugation/deconjugation in NF-κB signaling is frequently found in various human cancer types [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Song

Lin²,

Gong³

et al. 2012

Cell Res

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“…Although K63-linked polyubiquitination was mainly found as nondegradative modification controlling protein function for example during signal transduction, K48-linked ubiquitination typically targets proteins for degradation by the 26 S proteasome (20,21). Similar to other ubiquitin ligases, we found that MIB2 overexpression mediates autopolyubiquitination, reflecting catalytic activity (Fig.…”

Section: Mib2 Supports Synthesis Of K48-and K63-linked Polyubiquitinsupporting

confidence: 49%

“…Chains-Polyubiquitination as post-translational modification is well characterized (20,21). Although K63-linked polyubiquitination was mainly found as nondegradative modification controlling protein function for example during signal transduction, K48-linked ubiquitination typically targets proteins for degradation by the 26 S proteasome (20,21).…”

Section: Mib2 Supports Synthesis Of K48-and K63-linked Polyubiquitinmentioning

confidence: 99%

The E3 Ubiquitin Ligase Mind Bomb-2 (MIB2) Protein Controls B-cell CLL/Lymphoma 10 (BCL10)-dependent NF-κB Activation

Stempin

Chi

Giraldo-Vela

et al. 2011

Journal of Biological Chemistry

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Background: BCL10 is an essential molecule for the activation of the transcription factor NF-B in numerous immune receptor signaling pathways. Results: Identification of the E3 ubiquitin ligase MIB2 as part of the activated BCL10 complex controlling NF-B activity. Conclusion: MIB2 mediates BCL10-dependent NF-B activation. Significance: Identification of MIB2 as a regulator of important immune receptor signaling pathways.

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“…Alternatively, conjugation of linear polyubiquitin chains to NEMO by a linear ubiquitin chain assembly complex (LUBAC), comprised of heme-oxidized IRP2 ubiquitin ligase 1 homolog (HOIL-1), HOIL-1-interacting protein, and shankassociated RH domain-interacting protein (SHARPIN), is responsible for activation of NF-kB (4,5). Furthermore, K63-linked polyubiquitin chains are also reported to be essential for the activation of NF-kB and MAPKs (3,6,7). In response to TLR stimulation, TNFR-associated factor (TRAF)6 has been shown to catalyze K63-linked polyubiquitination by acting as an E3 ubiquitin ligase.…”

mentioning

confidence: 99%

Essential Roles of K63-Linked Polyubiquitin-Binding Proteins TAB2 and TAB3 in B Cell Activation via MAPKs

Ori

Kato

Sanjo

et al. 2013

The Journal of Immunology

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Polyubiquitination of proteins plays a critical role in the activation of immune cells. K63-linked polyubiquitin-binding proteins TGF-β–activated kinase 1 (TAK1)–binding protein (TAB)2 and TAB3 are implicated in NF-κB signaling via TAK1 activation. However, TAB2 alone is dispensable for NF-κB activation in embryonic fibroblasts, and the functional roles of TAB2 and TAB3 in immune cells has yet to be clarified. In this study, we demonstrate that TAB2 and TAB3 are essential for B cell activation leading to Ag-specific Ab responses, as well as B-1 and marginal zone B cell development. TAB2 and TAB3 are critical for the activation of MAPKs, especially ERK, but not NF-κB, in response to TLR and CD40 stimulation in B cells. Surprisingly, TAB2 and TAB3 are dispensable for TAK1 activation in B cells, indicating that TAB2 and TAB3 activate MAPKs via a pathway independent of TAK1. In contrast to B cells, macrophages lacking TAB2 and TAB3 did not show any defects in the cytokine production and the signaling pathway in response to TLR stimulation. Furthermore, TAB2 and TAB3 were dispensable for TNF-induced cytokine production in embryonic fibroblasts. Thus, TAB2- and TAB3-mediated K63-linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1/NF-κB axis.

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Signaling to NF- B: Regulation by Ubiquitination

Cited by 269 publications

References 90 publications

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

The E3 Ubiquitin Ligase Mind Bomb-2 (MIB2) Protein Controls B-cell CLL/Lymphoma 10 (BCL10)-dependent NF-κB Activation

Essential Roles of K63-Linked Polyubiquitin-Binding Proteins TAB2 and TAB3 in B Cell Activation via MAPKs

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