Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway

Korherr, Christian; Gille, Hendrik; Schäfer, Rolf; Koenig-Hoffmann, Kerstin; Dixelius, Johan; Egland, Kristi A.; Pastan, Ira; Brinkmann, Ulrich

doi:10.1073/pnas.0511319103

Cited by 95 publications

(89 citation statements)

References 28 publications

(41 reference statements)

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“…It is activated by infection of a number of viruses, including SV40, Ebola, influenza, Sendai, and human Our results suggest that TBK1 participates in cell proliferation and cell survival by regulating Akt. In fact, TBK1 has been reported to promote tumor growth and proliferation of HUVECs (27). Hasan et al (28) reported that TRIF/TBK1 regulates phosphorylation of the cell cycle inhibitor p27 kip1 and proteasome degradation.…”

Section: Discussionmentioning

confidence: 99%

Akt Contributes to Activation of the TRIF-Dependent Signaling Pathways of TLRs by Interacting with TANK-Binding Kinase 1

Joung

Park²,

Rani³

et al. 2011

The Journal of Immunology

115

116

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Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF) is an adaptor molecule that is recruited to TLR3 and -4 upon agonist stimulation and triggers activation of IFN regulatory factor 3 (IRF3) and expression of type 1 IFNs, which are critical for cellular antiviral responses. We show that Akt is a downstream molecule of TRIF/TANK-binding kinase 1 (TBK1) and plays an important role in the activation of IRF3 by TLR3 and -4 agonists. Blockade of Akt by a dominant-negative mutant or by short interfering RNA decreased IRF3 activation and IFN-β expression induced by polyinosinic:polycytidylic acid [poly(I:C)], LPS, TRIF, and TBK1. Association of endogenous TBK1 and Akt was observed in macrophages when stimulated with poly(I:C) and LPS. In vitro kinase assays combined with reversed-phase liquid chromatography mass spectrometry analysis showed that TBK1 enhanced phosphorylation of Akt on Ser473, whereas knockdown of TBK1 expression by short interfering RNA in macrophages decreased poly(I:C)- and LPS-induced Akt phosphorylation. Embryonic fibroblasts derived from TBK1 knockout mice also showed impaired Akt phosphorylation in response to poly(I:C) and LPS. To our knowledge, our results demonstrate a new regulatory mechanism for Akt activation mediated by TBK1 and a novel role of Akt in TLR-mediated immune responses.

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Section: Discussionmentioning

confidence: 99%

Akt Contributes to Activation of the TRIF-Dependent Signaling Pathways of TLRs by Interacting with TANK-Binding Kinase 1

Joung

Park²,

Rani³

et al. 2011

The Journal of Immunology

115

116

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“…CRMP1 is a suppressor of tumor cell invasion of the local stroma and might be a functional modulator of the Wnt signaling pathway in vivo (17,18). As the trigger of TBK-1 pathway, TBK1 is important for tumor angiogenesis and tumor-associated microvascular inflammation and expressed at significant levels in many solid tumors (19,20). A recent study has demonstrated that SEPT7 could function in gliomagenesis and in the suppression of glioma cell proliferation (21).…”

Section: Discussionmentioning

confidence: 99%

The expression and functional characterization associated with cell apoptosis and proteomic analysis of the novel gene MLAA-34 in U937 cells

Zhang

et al. 2012

Oncology Reports

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Abstract. MLAA-34 is a novel acute monocytic leukemia (M5)-associated antigen (MLAA) that plays a role in the apoptosis of U937 cells. However, the expression and molecular mechanism of MLAA-34 in U937 cells remain largely unclear. Here, we utilized three strategies to gain insight into the expression and molecular functions of MLAA-34 and to identify its interacting proteins and pathways involved in the fine-tuning of the MLAA-34 response. Western blot analysis was performed to assess the expression of MLAA-34 in 41 cell lines and five mixed cell types, which revealed that MLAA-34 is most strongly expressed in U937 cells. Immunostaining indicated that MLAA-34 is localized in the cytoplasm and cell membrane. Furthermore, lentivirus-mediated overexpression of MLAA-34 in the U937 cell line led to significant suppression of apoptosis and increased the potential of tumorigenicity. Co-immunoprecipitation (Co-IP), shotgun and bioinformatic analysis identified 256 proteins and 225 of them were annotated by gene ontology categories. This analysis revealed 71 proteins involved in cell apoptosis or proliferation of biological processes and signaling pathways. Moreover, the effect of MLAA-34 apoptosis may be through interaction with the Ras, Wnt, calcium and chemokine signaling pathways and thirteen of the annotated proteins may interact with MLAA-34 and participate in carcinogenesis directly. This study provides a basis for a better understanding of the molecular mechanism and proteomics in the inhibition of apoptosis by MLAA-34 in U937 cells and indicates that MLAA-34 may be a potential candidate for the early diagnosis and therapeutic application of M5.

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“…This protein is expressed in various rodent tissues such as stomach, small intestine, lung, testis, skin, brain, heart, kidney, spleen, thymus, and liver (Pomerantz & Baltimore 1999) and appears to be activated by phorbol esters, tumor promoters and growth factors (Tojima et al 2000). The known functions of TBK1 are related with the development of the innate antiviral response (Harris et al 2006) and with tumor angiogenesis (Korherr et al 2006). In the present report, we confirmed that TNF-a is directly associated with the induction of TBK1 in liver, first by showing that in OZRs large hepatic TBK1 levels coexist with increased levels of TNF-a and second by showing that rats infused by 4 h with TNF-a displayed large levels of association of this enzyme with the IR.…”

Section: Discussionmentioning

confidence: 99%

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

Muñoz

Giani²,

Mayer³

et al. 2009

Journal of Endocrinology

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The IkB kinase-b (IKK-b)/nuclear factor-kB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3b. This was accompanied by a decrease in phosphorylation of IR on serine (Ser) 994, a residue that seems to be implicated in the regulation of IR kinase in OZR. In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. TBK1 was found to co-immunoprecipitate with the IR, in the liver of OZR supporting an in vivo association between the IR and TBK1. Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes.

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Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway

Cited by 95 publications

References 28 publications

Akt Contributes to Activation of the TRIF-Dependent Signaling Pathways of TLRs by Interacting with TANK-Binding Kinase 1

Akt Contributes to Activation of the TRIF-Dependent Signaling Pathways of TLRs by Interacting with TANK-Binding Kinase 1

The expression and functional characterization associated with cell apoptosis and proteomic analysis of the novel gene MLAA-34 in U937 cells

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

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