Involvement of the Gab2 scaffolding adapter in type I interferon signalling

Baychelier, Florence; Nardeux, Pierre; Cajean-Feroldi, Chantal; Ermonval, Myriam; Guymarho, Jacqueline; Tovey, Michaël G.; Eid, Pierre

doi:10.1016/j.cellsig.2007.05.011

Cited by 12 publications

(7 citation statements)

References 34 publications

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“…3B and C). This may be due to the fact that while IFNAR-2 holds only ligand-binding capacities, IFNAR-1, mainly inducing the intracellular signaling cascades, has also been described to have weak ligand binding activity, too, and may interact with other proteins in the absence of IFNAR-2 (39,40). Alternatively, although both siRNA pools reduced receptor mRNA expression to a similar extend (Fig.…”

Section: Discussionmentioning

confidence: 96%

Interferon-β Induces Loss of Spherogenicity and Overcomes Therapy Resistance of Glioblastoma Stem Cells

Happold

Roth

Silginer

et al. 2014

Molecular Cancer Therapeutics

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Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O 6 -methylguanine DNA methyltransferase (MGMT) exhibit a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-b and respond to IFN-b with induction of STAT-3 phosphorylation. Exposure to IFN-b induces a minor loss of viability, but strongly interferes with sphere formation in GIC cultures. Furthermore, IFN-b sensitizes LTL and GIC to temozolomide and irradiation. RNA interference confirmed that both IFN-b receptors, R1 and R2, are required for IFN-b-mediated sensitization, but that sensitization is independent of MGMT or TP53. Most GIC lines are highly temozolomide-resistant, mediated by MGMT expression, but nevertheless susceptible to IFN-b sensitization. Gene expression profiling following IFN-b treatment revealed strong upregulation of IFN-b-associated genes, including a proapoptotic gene cluster, but did not alter stemness-associated expression signatures. Caspase activity and inhibition studies revealed the proapoptotic genes to mediate glioma cell sensitization to exogenous death ligands by IFN-b, but not to temozolomide or irradiation, indicating distinct pathways of death sensitization mediated by IFN-b. Thus, IFN-b is a potential adjunct to glioblastoma treatment that may target the GIC population. IFN-b operates independently of MGMT-mediated resistance, classical apoptosis-regulatory networks, and stemness-associated gene clusters. Mol Cancer Ther; 13(4); 948-61. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 96%

Interferon-β Induces Loss of Spherogenicity and Overcomes Therapy Resistance of Glioblastoma Stem Cells

Happold

Roth

Silginer

et al. 2014

Molecular Cancer Therapeutics

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“…Mouse anti-IFNAR1 mAb 34F10 and 64G12 and mouse anti-IFNAR2 mAbs 8F11 and 10E10 were described previously (13). Mouse anti-IFNAR1 mAb AA3 and EA12 were the kind gifts from Biogen Inc. (Boston).…”

Section: Methodsmentioning

confidence: 99%

“…Recent data indicate that signal transduction through the Jak/Stat pathway cannot fully account for the diversity and complexity of the biological response elicited by type I IFNs (12), and that other factors, for example receptor configuration and alternate signaling pathways, have to be considered (13). We recently showed that endocytosis plays an important role in the control of IFN-␣ signaling and biological activity (14).…”

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confidence: 99%

Palmitoylation of Interferon-α (IFN-α) Receptor Subunit IFNAR1 Is Required for the Activation of Stat1 and Stat2 by IFN-α

Claudinon

Gonnord

Beslard

et al. 2009

Journal of Biological Chemistry

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Type I interferons (IFNs) bind IFNAR receptors and activate Jak kinases and Stat transcription factors to stimulate the transcription of genes downstream from IFN-stimulated response elements. In this study, we analyze the role of protein palmitoylation, a reversible post-translational lipid modification, in the functional properties of IFNAR. We report that pharmacological inhibition of protein palmitoylation results in severe defects of IFN receptor endocytosis and signaling. We generated mutants of the IFNAR1 subunit of the type I IFN receptor, in which each or both of the two cysteines present in the cytoplasmic domain are replaced by alanines. We show that cysteine 463 of IFNAR1, the more proximal of the two cytoplasmic cysteines, is palmitoylated. A thorough microscopic and biochemical analysis of the palmitoylation-deficient IFNAR1 mutant revealed that IFNAR1 palmitoylation is not required for receptor endocytosis, intracellular distribution, or stability at the cell surface. However, the lack of IFNAR1 palmitoylation affects selectively the activation of Stat2, which results in a lack of efficient Stat1 activation and nuclear translocation and IFN-␣-activated gene transcription. Thus, receptor palmitoylation is a previously undescribed mechanism of regulating signaling activity by type I IFNs in the Jak/Stat pathway.Type I interferons (IFN 7 ␣/␤) are potent cellular mediators essential for several key cell functions, including immunomodulatory, antiviral, and antiproliferative activities. These pleiotropic effects occur through the transcriptional regulation of many IFN-stimulated genes (ISGs) (1). IFN signal transduction relies mainly on the activation of the Janus tyrosine kinase (Jak)/signal-transducing activators of transcription (Stat) pathways, although several other signaling cascades have also been associated with IFN-regulated transcription (2, 3). In general, the binding of type I IFNs to the cell surface receptor IFNAR1 and IFNAR2 subunits induces tyrosine phosphorylation in trans of the IFNAR-associated Jak kinases (Tyk2 with IFNAR1 and Jak1 with IFNAR2), which in turn leads to IFNAR tyrosine phosphorylation. Several members of the Stat family can be activated by type I IFNs, and Stat1 and Stat2 are the main downstream effectors of the type I IFN transcriptional response. Upon IFN-␣ stimulation, cytosolic Stat2 is recruited to the activated IFNAR complex where it becomes tyrosine-phosphorylated by the receptor-associated Jak kinases. Stat2 activation is a key event in IFN-␣ signaling because it is required for the indirect recruitment, through binding to Stat2, of Stat1 to IFNAR1 and its activation. There is some debate as to whether cytosolic Stat2 is preferentially recruited to IFNAR1 or to IFNAR2 (4 -9). Whereas the SH2 domain of Stat2 binds to a region surrounding the phosphorylated tyrosine 466 of IFNAR1, Stat2 can bind to IFNAR2 whether it is tyrosine-phosphorylated or not. This series of sequential tyrosine phosphorylations precedes the translocation of the IFN-stimulated gene factor 3...

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“…24 Cells were lysed with NET buffer (150 mM NaCl, 50 mM Tris pH 7.4, 5 mM EDTA) containing 1% Tx-100, and protease inhibitor cocktails (Thermo Scientific), and subsequently centrifuged. Biotinylation of cell surface proteins was performed on cells incubated with 0.25 mg/mL EZ-link sulfo-NHS-LC-biotin (Pierce).…”

Section: Western Blot and Immunoprecipitation Analysismentioning

confidence: 99%

Identification of a cellular ligand for the natural cytotoxicity receptor NKp44

Baychelier

Sennepin

Ermonval

et al. 2013

Blood

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147

133

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Key Points• The cellular ligand of the NKp44L is a novel isoform of the mixed-lineage leukemia-5 protein.• NKp44L is not expressed on healthy cells, but on tumor and transformed cells, rendering them more sensitive for the NK cytotoxicity.With an array of activating and inhibitory receptors, natural killer (NK) cells are involved in the eradication of infected, transformed, and tumor cells. NKp44 is a member of the natural cytotoxicity receptor family, which is exclusively expressed on activated NK cells. Here, we identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. The sharply decreased NK lysis activity induced by anti-NKp44L antibodies directly demonstrates the role of NKp44L in cytotoxicity. Taken together, these results show that NKp44L could be critical for NK cellmediated innate immunity. The identification and cellular distribution of NKp44L highlight the role of this self-molecule as a danger signal to alert the NK cell network. (Blood. 2013; 122(17):2935-2942

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Involvement of the Gab2 scaffolding adapter in type I interferon signalling

Cited by 12 publications

References 34 publications

Interferon-β Induces Loss of Spherogenicity and Overcomes Therapy Resistance of Glioblastoma Stem Cells

Interferon-β Induces Loss of Spherogenicity and Overcomes Therapy Resistance of Glioblastoma Stem Cells

Palmitoylation of Interferon-α (IFN-α) Receptor Subunit IFNAR1 Is Required for the Activation of Stat1 and Stat2 by IFN-α

Identification of a cellular ligand for the natural cytotoxicity receptor NKp44

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