Role of p38α Map Kinase in Type I Interferon Signaling

Li, Yongzhong; Sassano, Antonella; Majchrzak, Beata; Deb, Dilip K.; Levy, David E.; Gaestel, Matthias; Nebreda, Ángel R.; Fish, Eleanor N.; Platanias, Leonidas C.

doi:10.1074/jbc.m309927200

Cited by 113 publications

(121 citation statements)

References 63 publications

(102 reference statements)

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“…Importantly, the induction of IFN-dependent antiviral effects was strongly enhanced in 4E-BP1 knock-out MEFs, demonstrating that the 4E-BP1 protein plays an important regulatory role in the generation of IFN responses. Similar studies were performed to examine the role of TSC2 (tuberin), a negative regulator of mTOR activation (19,40) Altogether, our data provide direct evidence for a link between IFN-activated JAK-STAT pathways and the IFNinducible mTOR pathway. Although these pathways are activated independently of each other and mTOR inhibition does not affect the formation of STAT complexes and gene transcription (23,24), it appears that they cooperate in the control of common biological responses via regulation of expression of common protein mediators.…”

Section: Discussionmentioning

confidence: 48%

“…Antiviral Assays-The antiviral effects of mouse IFN␣ on mouse embryonic fibroblasts were determined by assaying its activity against encephalomyocarditis virus (EMCV) infection as in our previous studies (19).…”

Section: Methodsmentioning

confidence: 99%

“…IFN-dependent gene transcription, via a STAT-independent mechanism (17)(18)(19)(20). Although the precise mechanisms by which this signaling cascade facilitates gene transcription remain unknown, there is strong evidence implicating this pathway in the generation of the growth-inhibitory properties of IFN␣ on normal and leukemic hematopoietic cells as well as in the induction of antiviral responses (19 -22).…”

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confidence: 99%

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Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

Kaur

Lal

Sassano

et al. 2007

Journal of Biological Chemistry

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106

132

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The mechanisms regulating initiation of mRNA translation for the generation of protein products that mediate interferon (IFN) responses are largely unknown. We have previously shown that both Type I and II IFNs engage the mammalian target of rapamycin (mTOR), resulting in downstream phosphorylation and deactivation of the translational repressor 4E-BP1 (eIF4E-binding protein 1). In the current study, we provide direct evidence that such regulation of 4E-BP1 by IFN␣ or IFN␥ results in sequential dissociation of 4E-BP1 from eukaryotic initiation factor-4E and subsequent formation of a functional complex between eukaryotic initiation factor-4E and eukaryotic initiation factor-4G, to allow initiation of mRNA translation. We also demonstrate that the induction of key IFN␣-or IFN␥-inducible proteins (ISG15 (interferon-stimulated Type I (␣, ␤, ␦, ⑀, , and ) and II (␥) interferons (IFNs) 2 are pleiotropic cytokines that exhibit important antiviral, immunomodulatory, and growth inhibitory properties via engagement of widely expressed cell surface-specific receptors (1-5). The IFNs constitute the first line of the immune antiviral defense and are key components of the immune surveillance against tumors (1-5). In addition, because of their important biological properties, different recombinant IFNs (␣, ␤, and ␥) have been used extensively as therapeutic agents in a variety of clinical syndromes in humans, and certain IFN-subtypes are approved for the treatment of human malignancies, viral syndromes, and neurologic diseases (6 -10).Over the years, the mechanisms of IFN signal transduction have been the focus of attention by many research groups and have come under extensive investigation. Since the demonstration of the existence of STAT pathways that regulate transcription of interferon-inducible genes (2, 3), there has been gradual accumulation of evidence pointing toward a complicated network of multiple signaling pathways, whose coordinated function is necessary for the generation of IFN biological responses (4, 5). For instance, it has now become apparent that, in addition to different combinations of IFN-activated JAKs and STATs, the coordinated function of the phosphatidylinositol (PI) 3-kinase and the p38 mitogen-activated protein kinase pathways are essential for optimal IFN-dependent transcriptional regulation (5). The PI 3Ј-kinase pathway appears to be required for IFN-inducible transcriptional activation by regulating phosphorylation of STAT1 on serine 727 (11, 12), probably via intermediate engagement and activation of protein kinase C-␦ (13-16). Activation of the p38 mitogen-activated protein kinase appears to be also necessary for Type I, but not II, * This work was supported by National Institutes of Health Grants CA77816, CA100579, and CA94079 (to L. C. P.), by a grant from the Department of Veterans Affairs (to L. C. P.), and Canadian Institutes of Health Research Grant MOP15094 (to E. N. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article mus...

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Section: Discussionmentioning

confidence: 48%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

Kaur

Lal

Sassano

et al. 2007

Journal of Biological Chemistry

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106

132

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“…Although the biological effects associated with type I IFN were originally thought to be mediated solely through the classical JAK/STAT pathway (29), it is now clear that many other signaling cascades, including MAPK and PI3K/Akt pathways, are activated either independently or in parallel after IFNAR ligation, and cooperation between pathways is essential for complete transcriptional activation of target genes (32). Both pharmacological inhibition and gene ablation studies show a critical role for p38 pathways in transcriptional regulation of type I IFN-stimulated genes (37,38). The MEK/ERK pathway is also activated downstream of IFNAR signals (39), and type I IFN-induced AP-1 activation in primary human microglia requires ERK activation (39).…”

Section: Discussionmentioning

confidence: 99%

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Poovassery

Bishop

2012

The Journal of Immunology

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Toll-like receptor 7 (TLR7) signals to B cells are critically involved in the innate immune response to microbes, as well as pathogenesis of autoimmune diseases, but the molecular mechanisms that normally regulate these responses are incompletely understood. We previously reported that repeated stimulation through TLR7 induces a state of hyporesponsiveness (TLR tolerance) in both human and mouse B cells, characterized by marked inhibition of particular signaling pathways. BCR signals prevent and overcome TLR7 tolerance. Because optimal responses to TLR7 in B cells require type I IFN, we investigated whether BCR-mediated effects on TLR7 tolerance are mediated by type I IFN receptor (IFNAR) signals. Surprisingly, although BCR-mediated reversal of TLR7 tolerance was IFNAR independent, IFNAR signals alone also blocked TLR7 tolerance, despite enhancing TLR7 expression. Both BCR and IFNAR signals restored the phosphorylation of the transcriptional regulator c-Jun, but only BCR signals blocked the tolerance-mediated inhibition of JNK. Both BCR and IFNAR-mediated regulation was dependent on activation of the PI3K/Akt/mammalian target of rapamycin signaling pathway, indicating a central role for this axis in integrating TLR7, BCR, and IFNAR signals in B cells. These new findings reveal distinct and overlapping signaling mechanisms used by BCR and IFNAR in the regulation of TLR7 tolerance and activation.

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“…Engagemnet of the Type I IFNR results in activation of p38 MAPK in a Rac1- and MKK6-dependent manner [80–82], and such activation is ultimately required for optimal Type I IFN-mediated gene transcription and generation of the biological effects of Type I IFNs [82–85]. In the case of type II IFNs, engagement of the p38 MAPK is not required for transcription via GAS elements [86] but is essential for mediating its anti-proliferative responses on primitive hematopoietic cells [87]. …”

Section: Rantesmentioning

confidence: 99%

Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.

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Role of p38α Map Kinase in Type I Interferon Signaling

Cited by 113 publications

References 63 publications

Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Mnk kinases in cytokine signaling and regulation of cytokine responses

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