Smad6 negatively regulates interleukin 1-receptor–Toll-like receptor signaling through direct interaction with the adaptor Pellino-1

Choi, Kyung‐Chul; Lee, Youn Sook; Lim, Seunghwan; Choi, Ho Lim; Lee, Chang-Hun; Lee, Eunkyung; Hong, Seok Pyo; Kim, In-Hoo; Kim, Seong‐Jin; Park, Seok Hee

doi:10.1038/ni1383

Cited by 120 publications

(141 citation statements)

References 55 publications

Supporting

Mentioning

138

Contrasting

Order By: Relevance

“…Intriguingly, some studies have demonstrated that members of the Pellino family can be targeted by regulatory strategies to suppress TLR signalling [33,44,49]. Indeed, the role of Pellino3 as a direct negative regulator of innate immune signalling has already been described [33] (Figure 4a).…”

Section: Pellino Proteins As Novel Targets For Negative Regulation Ofmentioning

confidence: 98%

“…However, other reports have failed to detect any basal interactions between overexpressed MyD88 and Pellino proteins [37,47]. Many groups have described associations of each of the Pellino proteins with TRAF6 and these interactions are strongly promoted by IL-1R signalling [33,36,37,41,44,47]. The nature of these interactions remains to be defined with no available data to date to indicate whether Pellino proteins interact directly with TRAF-6 or indirectly as part of a larger protein complex.…”

Section: Pellino Proteins Interact With Other Tlr and Il1-r Signallinmentioning

confidence: 99%

“…There are contrasting reports on the ability of overexpressed Pellino1 protein to induce a NF-kB-regulated reporter gene [10,44], however, these same groups have shown that suppression of endogenous Pellino1 by siRNAs impairs IL-1-induced activation of NF-kB in a human [36] and murine [44] cell line. Furthermore, suppression of Pellino1 strongly inhibits the ability of IL-1 to induce the NF-kB-responsive gene IL-8 [36].…”

Section: Pellino1mentioning

confidence: 99%

“…Furthermore, a yeast two-hybrid screen using IRAK4 as bait independently identified Pellino2 as a protein-binding partner [40]. Under physiological conditions, the Pellino-IRAK interactions are likely to be dependent on prior TLR or IL-1R stimulation because endogenous IRAK-Pellino associations are not observed in resting cells but manifest in response to stimulation by IL-1 [33,[35][36][37]44] and LPS [44].…”

Section: Irak Polyubiquitylation and Tlr/il-1r Signallingmentioning

confidence: 99%

“…None of the Pellino proteins have been reported to interact with TLR or IL-1R complexes, however, one report indicates that IL-1 signalling can promote the interaction of overexpressed Pellino1 with MyD88 [44]. However, other reports have failed to detect any basal interactions between overexpressed MyD88 and Pellino proteins [37,47].…”

Section: Pellino Proteins Interact With Other Tlr and Il1-r Signallinmentioning

confidence: 99%

See 4 more Smart Citations

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

Moynagh

2009

Trends in Immunology

132

102

View full text Add to dashboard Cite

Section: Pellino Proteins As Novel Targets For Negative Regulation Ofmentioning

confidence: 98%

Section: Pellino Proteins Interact With Other Tlr and Il1-r Signallinmentioning

confidence: 99%

Section: Pellino1mentioning

confidence: 99%

Section: Irak Polyubiquitylation and Tlr/il-1r Signallingmentioning

confidence: 99%

Section: Pellino Proteins Interact With Other Tlr and Il1-r Signallinmentioning

confidence: 99%

See 3 more Smart Citations

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

Moynagh

2009

Trends in Immunology

132

102

View full text Add to dashboard Cite

Regulation of RANKL-induced osteoclastogenesis by TGF-β through molecular interaction between Smad3 and Traf6

Yasui¹,

Kadono²,

Nakamura³

et al. 2011

Journal of Bone and Mineral Research

101

View full text Add to dashboard Cite

Previous studies have shown that transforming growth factor b (TGF-b) promotes receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis. However, the underlying molecular mechanisms have not been elucidated. When TGF-b signals were blocked either by a specific inhibitor of TGF-b type 1 receptor kinase activity, SB431542, or by introducing a dominant-negative mutant of TGF-b type 2 receptor, RANKL-induced osteoclastogenesis was almost completely suppressed. Blockade of Smad signaling by overexpression of Smad7 or c-Ski markedly suppressed RANKL-induced osteoclastogenesis, and retroviral induction of an activated mutant of Smad2 or Smad3 reversed the inhibitory effect of SB431542. Immunoprecipitation analysis revealed that Smad2/3 directly associates with the TRAF6-TAB1-TAK1 molecular complex, which is generated in response to RANKL stimulation and plays an essential role in osteoclast differentiation. TRAF6-TAB1-TAK1 complex formation was not observed when TGF-b signaling was blocked. Analysis using deletion mutants revealed that the MH2 domain of Smad3 is necessary for TRAF6-TAB1-TAK1 complex formation, downstream signal transduction, and osteoclast formation. In addition, gene silencing of Smad3 in osteoclast precursors markedly suppressed RANKLinduced osteoclast differentiation. In summary, TGF-b is indispensable in RANKL-induced osteoclastogenesis, and the binding of Smad3 to the TRAF6-TAB1-TAK1 complex is crucial for RANKL-induced osteoclastogenic signaling. ß

show abstract

The role of transforming growth factor‐beta in immune suppression and chronic inflammation of squamous cell carcinomas

Strait

Wang

2020

Molecular Carcinogenesis

View full text Add to dashboard Cite

Despite a decline in the incidence of squamous cell carcinomas (SCCs) over the past 20 years, their survival rate has remained nearly the same, indicating that treatment options have not improved relative to other cancer types. Immunotherapies have a high potential for a sustained effect in SCC patients, but their response rate is low.Here, we review the suppressive role of transforming growth factor-beta (TGFβ) on the antitumor immune response in SCC and present its potential as a therapeutic target in combination with the current range of immunotherapies available for SCC patients. We conclude that SCCs are an optimal cancer type to study the effectiveness of TGFβ inhibition due to the prevalence of dysregulated TGFβ signaling in them. K E Y W O R D S head and neck squamous cell carcinoma, immune checkpoint blockade, immunotherapy, tumor microenvironment 1 | INTRODUCTION Squamous cell carcinomas (SCCs) are cancers that arise from areas of stratified epithelium and are primarily found in the skin, lung, and the epithelial lining of the oropharyngeal and nasopharyngeal cavities.Although skin SCC incidence cannot be estimated because most cancer registries do not collect data on it, deaths associated with nonmelanoma skin cancer, which is primarily SCC, exceed melanoma deaths due to the high number of SCC cases. 1 Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and accounts for 53,000 new cases each year in the United States. 2 Although its incidence has decreased slightly, its mortality rate has slightly increased since 2012, 2 indicating that current therapeutic options for patients with HNSCC have stagnated and novel therapeutics have not yet improved the majority of patient outcomes. The current standard of care is a combination of radiotherapy, surgery, and chemotherapy; patients who do not respond to those typically have incurable recurring metastatic disease. The primary causes of HNSCC are either HPV or heavy tobacco and alcohol use. HPV -HNSCCs are associated with worse prognoses and a less inflammatory immune microenvironment. 3It is long established that mutagen-induced SCC results in elevated levels of secreted transforming growth factor-beta (TGFβ) in the tumor microenvironment. 4 The TGFβ signaling pathway has been reviewed in depth elsewhere, 5,6 and is summarized here in Figure 1.Briefly, when the TGFβ receptor complex binds TGFβ ligand, it phosphorylates receptor-associated Smad2 and Smad3 proteins. Smad2 and Smad3 form a complex with Smad4, which translocates to the nucleus, binds to Smad binding elements on genetic loci, and regulates numerous transcriptional pathways. The TGFβ receptor complex also activates numerous noncanonical signaling pathways independently of Smad proteins. In tobacco and alcohol-associated cases, HNSCC is often preceded by dysregulation of TGFβ signaling, resulting in elevated levels of TGFβ within a tumor while tumor cells Abbreviations: CAF, cancer-associated fibroblast; CTL, cytotoxic T lymphocyte; HNSCC, head and neck squamous ...

show abstract

Smad6 negatively regulates interleukin 1-receptor–Toll-like receptor signaling through direct interaction with the adaptor Pellino-1

Cited by 120 publications

References 55 publications

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

Regulation of RANKL-induced osteoclastogenesis by TGF-β through molecular interaction between Smad3 and Traf6

The role of transforming growth factor‐beta in immune suppression and chronic inflammation of squamous cell carcinomas

Contact Info

Product

Resources

About