LATS2 inhibits the activity of NF-κ B signaling by disrupting the interaction between TAK1 and IKKβ

Yao, Feng; Zhou, Weizheng; Zhong, Caiyun; Fang, Wentao

doi:10.1007/s13277-015-3362-x

Cited by 7 publications

(4 citation statements)

References 19 publications

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“…LATS2 promotes apoptosis by shunting p53 to pro-apoptotic promoters (Aylon et al 2010). LATS2 is also known to function as a negative regulator of TNF-α-induced NF-κB activation (Yao et al 2015). CHAF1B is involved in epigenetic control of chromatin dynamics during cell cycling, and its inhibition leads to apoptosis and accumulation of double-strand breaks (Nabatiyan and Krude 2004).…”

Section: Discussionmentioning

confidence: 99%

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Saeed

2017

Immunogenetics

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Systemic lupus erythematosus (SLE) is a complex disorder. Genetic association studies of complex disorders suffer from the following three major issues: phenotypic heterogeneity, false positive (type I error), and false negative (type II error) results. Hence, genes with low to moderate effects are missed in standard analyses, especially after statistical corrections. OASIS is a novel linkage disequilibrium clustering algorithm that can potentially address false positives and negatives in genome-wide association studies (GWAS) of complex disorders such as SLE. OASIS was applied to two SLE dbGAP GWAS datasets (6077 subjects; ∼0.75 million single-nucleotide polymorphisms). OASIS identified three known SLE genes viz. IFIH1, TNIP1, and CD44, not previously reported using these GWAS datasets. In addition, 22 novel loci for SLE were identified and the 5 SLE genes previously reported using these datasets were verified. OASIS methodology was validated using single-variant replication and gene-based analysis with GATES. This led to the verification of 60% of OASIS loci. New SLE genes that OASIS identified and were further verified include TNFAIP6, DNAJB3, TTF1, GRIN2B, MON2, LATS2, SNX6, RBFOX1, NCOA3, and CHAF1B. This study presents the OASIS algorithm, software, and the meta-analyses of two publicly available SLE GWAS datasets along with the novel SLE genes. Hence, OASIS is a novel linkage disequilibrium clustering method that can be universally applied to existing GWAS datasets for the identification of new genes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-017-0976-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Saeed

2017

Immunogenetics

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“…Given that NF-kB is involved in the poly I:C dependent upregulation of TSLP in NHBE cells [ 11 ], our results now provide additional evidence to support a role of the mTOR / NF-kB axis in the upregulation of TSLP in NHBE cells after poly I:C / IL-4 stimulation. This is based on the pharmacological profile of compound 4 , everolimus and AZD 8055 and is further supported by the profile of external hits: ouabain has been reported to downregulate the TNFα / NF-kB pathway [ 45 ], while the tumour suppressor LATS2, upregulated by nocodazole [ 49 ], has also been reported to inhibit NF-kB mediated signaling [ 59 ].…”

Section: Discussionmentioning

confidence: 97%

Application of a phenotypic drug discovery strategy to identify biological and chemical starting points for inhibition of TSLP production in lung epithelial cells

et al. 2018

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Thymic stromal lymphopoietin (TSLP) is a cytokine released by human lung epithelium in response to external insult. Considered as a master switch in T helper 2 lymphocyte (Th2) mediated responses, TSLP is believed to play a key role in allergic diseases including asthma. The aim of this study was to use a phenotypic approach to identify new biological and chemical starting points for inhibition of TSLP production in human bronchial epithelial cells (NHBE), with the objective of reducing Th2-mediated airway inflammation. To this end, a phenotypic screen was performed using poly I:C / IL-4 stimulated NHBE cells interrogated with a 44,974 compound library. As a result, 85 hits which downregulated TSLP protein and mRNA levels were identified and a representative subset of 7 hits was selected for further characterization. These molecules inhibited the activity of several members of the MAPK, PI3K and tyrosine kinase families and some of them have been reported as modulators of cellular phenotypic endpoints like cell-cell contacts, microtubule polymerization and caspase activation. Characterization of the biological profile of the hits suggested that mTOR could be a key activity involved in the regulation of TSLP production in NHBE cells. Among other targeted kinases, inhibition of p38 MAPK and JAK kinases showed different degrees of correlation with TSLP downregulation, while Syk kinase did not seem to be related. Overall, inhibition of TSLP production by the selected hits, rather than resulting from inhibition of single isolated targets, appeared to be due to a combination of activities with different levels of relevance. Finally, a hit expansion exercise yielded additional active compounds that could be amenable to further optimization, providing an opportunity to dissociate TSLP inhibition from other non-desired activities. This study illustrates the potential of phenotypic drug discovery to complement target based approaches by providing new chemistry and biology leads.

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“…Thus, SAMHD1 bound to these domains may result in affecting the kinase activity and the interaction between IκBα and IKKα or IKKβ. Some NF-κB inhibitors such as large tumor suppressor gene 2 (LATS2) and Nemo-like kinase (NLK) disrupt the interaction between TAK1 and IKKβ to inhibit NF-κB activation ( 40 , 41 ). SAMHD1 binds to IKKα and IKKβ directly, which may prevent the phosphorylation of IKKα and IKKβ by TAK1.…”

Section: Discussionmentioning

confidence: 99%

The host antiviral protein SAMHD1 suppresses NF-κB activation by interacting with the IKK complex during inflammatory responses and viral infection

Yang¹,

Espada²,

Phillips³

et al. 2023

Journal of Biological Chemistry

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LATS2 inhibits the activity of NF-κ B signaling by disrupting the interaction between TAK1 and IKKβ

Cited by 7 publications

References 19 publications

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Application of a phenotypic drug discovery strategy to identify biological and chemical starting points for inhibition of TSLP production in lung epithelial cells

The host antiviral protein SAMHD1 suppresses NF-κB activation by interacting with the IKK complex during inflammatory responses and viral infection

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