Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Cargnello, Marie; Roux, Philippe P.

doi:10.1128/mmbr.00031-10

Cited by 2,423 publications

(1,654 citation statements)

References 444 publications

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“…3B). RSKs phosphorylate protein substrates at serine or threonine residues within the motif RxRxxS/T (R, arginine; S, serine; T, threonine; x, any amino acid), identical to the well-characterized AKT phosphorylation motif (32)(33)(34). Therefore, we used a commercially available motif-specific antibody to determine the impact of ORF45-F66A mutation on gross phosphorylation of putative RSK substrates in KSHV-infected cells.…”

Section: Resultsmentioning

confidence: 99%

Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

Kuang

et al. 2015

J Virol

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We have previously shown that ORF45, an immediate-early and tegument protein of Kaposi's sarcoma-associated herpesvirus (KSHV), causes sustained activation of p90 ribosomal S6 kinases (RSKs) and extracellular regulated kinase (ERK) (E. Kuang, Q. Tang, G. G. Maul, and F. Zhu, J Virol 82:1838 -1850, 2008, http://dx.doi.org/10.1128/JVI.02119-07). We now have identified the critical region of ORF45 that is involved in RSK interaction and activation. Alanine scanning mutagenesis of this region revealed that a single F66A point mutation abolished binding of ORF45 to RSK or ERK and, consequently, its ability to activate the kinases. We introduced the F66A mutation into BAC16 (a bacterial artificial chromosome clone containing the entire infectious KSHV genome), producing BAC16-45F66A. In parallel, we also repaired the mutation and obtained a revertant, BAC16-45A66F. The reconstitution of these mutants in iSLK cells demonstrated that the ORF45-F66A mutant failed to cause sustained ERK and RSK activation during lytic reactivation, resulting in dramatic differences in the phosphoproteomic profile between the wildtype virus-infected cells and the mutant virus-infected cells. ORF45 mutation or deletion also was accompanied by a noticeable decreased in viral gene expression during lytic reactivation. Consequently, the ORF45-F66A mutant produced significantly fewer infectious progeny virions than the wild type or the revertant. These results suggest a critical role for ORF45-mediated RSK activation in KSHV lytic replication. IMPORTANCEKSHV is the causative agent of three human malignancies. KSHV pathogenesis is intimately linked to its ability to modulate the host cell microenvironment and to facilitate efficient production of progeny viral particles. We previously described the mechanism by which the KSHV lytic protein ORF45 activates the cellular kinases ERK and RSK. We now have mapped the critical region of ORF45 responsible for binding and activation of ERK/RSK to a single residue, F66. We mutated this amino acid of ORF45 (F66A) and introduced the mutation into a newly developed bacterial artificial chromosome containing the KSHV genome (BAC16). This system has provided us with a useful tool to characterize the functions of ORF45-activated RSK upon KSHV lytic reactivation. We show that viral gene expression and virion production are significantly reduced by F66A mutation, indicating a critical role for ORF45-activated RSK during KSHV lytic replication. K aposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), the most common malignancy in HIV-infected individuals (1, 2). Besides KS, KSHV is associated with two lymphoproliferative diseases, primary effusion lymphoma and multicentric Castleman's disease (3, 4). KSHV belongs to the Gammaherpesvirinae subfamily in the Herpesviridae family and is closely related to rhesus rhadinovirus (RRV), herpesvirus saimiri (HVS), and murine gammaherpesvirus 68 (MHV-68) in the Rhadinovirus genus (␥2). Its closest relative in humans is Epstein-...

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Section: Resultsmentioning

confidence: 99%

Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

Kuang

et al. 2015

J Virol

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“…The types of known MAPKs are extracellular signal-regulated kinase 1 and 2 (ERK 1/2), ERK 5, JNK 1–3, and p38 protein isoforms (p38α, β, γ, and δ) [153]. Among the MAPKs, p38 MAPKs regulate the expression of many cytokines [154].…”

Section: Mechanisms Of Action In Disease Preventionmentioning

confidence: 99%

Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits

Khoo

Azlan

Tang

et al. 2017

Food & Nutrition Research

1,793

1,327

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Anthocyanins are colored water-soluble pigments belonging to the phenolic group. The pigments are in glycosylated forms. Anthocyanins responsible for the colors, red, purple, and blue, are in fruits and vegetables. Berries, currants, grapes, and some tropical fruits have high anthocyanins content. Red to purplish blue-colored leafy vegetables, grains, roots, and tubers are the edible vegetables that contain a high level of anthocyanins. Among the anthocyanin pigments, cyanidin-3-glucoside is the major anthocyanin found in most of the plants. The colored anthocyanin pigments have been traditionally used as a natural food colorant. The color and stability of these pigments are influenced by pH, light, temperature, and structure. In acidic condition, anthocyanins appear as red but turn blue when the pH increases. Chromatography has been largely applied in extraction, separation, and quantification of anthocyanins. Besides the use of anthocyanidins and anthocyanins as natural dyes, these colored pigments are potential pharmaceutical ingredients that give various beneficial health effects. Scientific studies, such as cell culture studies, animal models, and human clinical trials, show that anthocyanidins and anthocyanins possess antioxidative and antimicrobial activities, improve visual and neurological health, and protect against various non-communicable diseases. These studies confer the health effects of anthocyanidins and anthocyanins, which are due to their potent antioxidant properties. Different mechanisms and pathways are involved in the protective effects, including free-radical scavenging pathway, cyclooxygenase pathway, mitogen-activated protein kinase pathway, and inflammatory cytokines signaling. Therefore, this review focuses on the role of anthocyanidins and anthocyanins as natural food colorants and their nutraceutical properties for health. Abbreviations: CVD: Cardiovascular disease VEGF: Vascular endothelial growth factor

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“…Febrile temperatures can induce HSP70 expression and release by regulating signal transduction pathways, such as the mitogen-activated protein kinase (MAPK) (Gupta et al 2013), extracellular regulated kinase 1/2 (ERK 1/2), p38, and c-Jun amino (N)-terminal kinases 1/2 (JNK 1/2) (Cargnello and Roux 2011).…”

Section: Introductionmentioning

confidence: 99%

The regulation of TNFα production after heat and endotoxin stimulation is dependent on Annexin-A1 and HSP70

Nair

Arora

Lim

et al. 2015

Cell Stress and Chaperones

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Febrile temperatures can induce stress responses which protect cells from damage and can reduce inflammation during infections and sepsis. However, the mechanisms behind the protective functions of heat in response to the bacterial endotoxin LPS are unclear. We have recently shown that Annexin-1 (ANXA1)-deficient macrophages exhibited higher TNFα levels after LPS stimulation. Moreover, we have previously reported that ANXA1 can function as a stress protein.Therefore in this study, we determined if ANXA1 is involved in the protective effects of heat on cytokine levels in macrophages after heat and LPS. Exposure of macrophages to 42°C for 1 h prior to LPS results in an inhibition of TNFα production, which was not evident in ANXA1 −/− macrophages. We show that this regulation involves primarily MYD88-independent pathways. ANXA1 regulates TNFα mRNA stability after heat and LPS, and this is dependent on endogenous ANXA1 expression and not exogenously secreted factors. Further mechanistic studies revealed the possible involvement of the heat shock protein HSP70 and JNK in the heat and inflammatory stress response regulated by ANXA1. This study shows that ANXA1, an immunomodulatory protein, is critical in the heat stress response induced after heat and endotoxin stimulation.

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Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases

Cited by 2,423 publications

References 444 publications

Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

Activation of p90 Ribosomal S6 Kinases by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Optimal Production of Infectious Viruses

Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits

The regulation of TNFα production after heat and endotoxin stimulation is dependent on Annexin-A1 and HSP70

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