Philip Cohen

University of Dundee, Dundee, Scotland, United Kingdom

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Publications (107)773.93 Total impact

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    ABSTRACT: Polo-Like Kinase (PLK) inhibitors, such as BI-2536, have been reported to suppress interferon β (IFNβ) gene transcription induced by ligands that activate TLR3 and TLR4. Here, we report that BI-2536 is likely to exert this effect by preventing the interaction of the transcription factors IRF3 and c-Jun with the IFNβ promoter, but without affecting the TANK-binding kinase 1 (TBK1)-catalysed phosphorylation of IRF3 at Ser396, the dimerization and nuclear translocation of IRF3 or the phosphorylation of c-Jun and ATF2. Although BI-2536 inhibits few other kinases tested, it interacts with Bromodomain and Extra-Terminal (BET) family members and displaces them from acetylated lysine residues on histones. We found that BET inhibitors that do not inhibit PLKs, phenocopied the effect of BI-2536 on IFNβ gene transcription. Similarly, BET inhibitors blocked the interaction of IRF5 with the IFNβ promoter and the secretion of IFNβ induced by TLR7 or TLR9 ligands in the human plasmacytoid dendritic cell line GEN2.2, but without affecting the nuclear translocation of IRF5. We found that the BET family member BRD4 was associated with the IFNβ promoter and that this interaction was enhanced by TLR3- or TLR4-ligation and prevented by BI-2536 and other BET inhibitors. Our results establish that BET family members are essential for TLR-stimulated IFNβ gene transcription by permitting transcription factors to interact with the IFNβ promoter. They also show that the interaction of the IFNβ promoter with BRD4 is regulated by TLR ligation and that BI-2536 is likely to suppress IFNβ gene transcription by targeting BET family members.
    Biochemical Journal 04/2015; DOI:10.1042/BJ20141523 · 4.78 Impact Factor
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    ABSTRACT: IntroductionThe link between cardiovascular disease (CVD) and patients suffering from chronic inflammation is not clearly understood. We examined a knock-in mouse expressing a poly-ubiquitin-binding-defective mutant of the protein ABIN1 (ABIN1(D485N)), which develops a systemic lupus erythematosus-like autoimmune disease due to the hyperactivation of IkB kinases (IKKs) and mitogen activated protein kinases (MAPK). These mice were used to determine the potential role of these signalling pathways in inflammation-mediated CVD development.Methods Laser Doppler imaging in combination with the iontophoresis of vasoactive chemicals were used to assess endothelium-dependent vasodilatation in vivo in ABIN1 (D485N)) mutant defective (n¿=¿29) and wild-type (WT) control (n¿=¿26) mice. Measurements were made at baseline and animals were subdivided to receive either chow or a pro-atherogenic diet for 4 weeks, after which follow-up assessments were made. Paired and unpaired t-tests, ANOVA with post-hoc bonferroni correction were used for statistical significance P <0.05.ResultsEndothelium-dependent vasodilatation to acetylcholine was attenuated at four weeks in ABIN1(D485N)-chow fed mice compared with age-matched WT-chow fed mice (P <0.05). The magnitude of attenuation was similar to that observed in WT-cholesterol fed animals (versus WT-chow, P <0.01). ABIN1(D485N)-cholesterol fed mice had the poorest endothelium-dependent responses compared with other groups (P <0.001). ABIN1(D485N)-chow fed mice had increased plasma interleukin-6 (IL-6) levels (versus WT-chow, P <0.001) and this was further elevated in ABIN1(D485N)-cholesterol fed mice (versus ABIN1(D485N)- chow P <0.05). IL-1alpha was significantly greater in all groups compared with WT-chow (P¿<¿0.01). ABIN1(D485N) mice showed significant cardiac hypertrophy (P <0.05).Conclusions The ABIN(D485N) mice display endothelial dysfunction and cardiac hypertrophy, which is possibly mediated through IL-6 and to a lesser degree IL-1alpha. These results suggest that the ABIN1-mediated hyper-activation of IKKs and MAPKs might mediate chronic inflammation and CVD development.
    Arthritis Research & Therapy 02/2015; 17(1):22. DOI:10.1186/s13075-015-0543-3 · 4.12 Impact Factor
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    ABSTRACT: The nuclear exosome targeting complex (NEXT) directs a major 3'-5' exonuclease, the RNA exosome, for degradation of nuclear noncoding (nc) RNAs. We identified the RNA-binding component of the NEXT complex, RBM7, as a substrate of p38(MAPK)/MK2-mediated phosphorylation at residue S136. As a result of this phosphorylation, RBM7 displays a strongly decreased RNA-binding capacity, while inhibition of p38(MAPK) or mutation of S136A in RBM7 increases its RNA association. Interestingly, promoter-upstream transcripts (PROMPTs), such as proRBM39, proEXT1, proDNAJB4, accumulated upon stress stimulation in a p38(MAPK)/MK2-dependent manner, a process inhibited by overexpression of RBM7(S136A). While there are no stress-dependent changes in RNA-polymerase II (RNAPII) occupation of PROMPT regions representing unchanged transcription, stability of PROMPTs is increased. Hence, we propose that phosphorylation of RBM7 by the p38(MAPK)/MK2 axis increases nuclear ncRNA stability by blocking their RBM7-binding and subsequent RNA exosome targeting to allow stress-dependent modulations of the noncoding transcriptome. © 2014 Tiedje et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.
    RNA 01/2015; 21(2-2):262-78. DOI:10.1261/rna.048090.114 · 4.62 Impact Factor
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    ABSTRACT: The siRNA knockdown of IFN Regulatory Factor 5 (IRF5) in the human plasmacytoid dendritic cell line Gen2.2 prevented IFNβ production induced by compound CL097, a ligand for Toll-like receptor 7 (TLR7). CL097 also stimulated the phosphorylation of IRF5 at Ser462 and stimulated the nuclear translocation of wild-type IRF5, but not the IRF5[Ser462Ala] mutant. The CL097-stimulated phosphorylation of IRF5 at Ser462 and its nuclear translocation was prevented by the pharmacological inhibition of protein kinase IKKβ or the siRNA knockdown of IKKβ or its "upstream" activator, the protein kinase TAK1. Similar results were obtained in a murine macrophage cell line stimulated with the TLR7 agonist compound R848 or the nucleotide oligomerization domain 1 (NOD1) agonist KF-1B. IKKβ phosphorylated IRF5 at Ser462 in vitro and induced the dimerization of wild-type IRF5 but not the IRF5[S462A] mutant. These findings demonstrate that IKKβ activates two "master" transcription factors of the innate immune system, IRF5 and NF-κB.
    Proceedings of the National Academy of Sciences 10/2014; 111(49). DOI:10.1073/pnas.1418399111 · 9.81 Impact Factor
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    ABSTRACT: We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure-activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.
    Journal of Medicinal Chemistry 07/2014; 58(1). DOI:10.1021/jm500480k · 5.48 Impact Factor
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    ABSTRACT: The IκB kinase β (IKKβ) is required to activate the transcription factor NF-κB, but how IKKβ itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more "upstream" protein kinases in some reports but by auto-phosphorylation in others. Here, we resolve this controversy by demonstrating that the activation of IKKβ induced by IL-1 or TNF in embryonic fibroblasts, or by ligands that activate Toll-Like receptors in macrophages, requires two distinct phosphorylation events; first, the TAK1-catalysed phosphorylation of Ser177 and second the IKKβ-catalyzed auto-phosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKKβ to phosphorylate exogenous substrates. We also provide genetic evidence which indicates that the IL-1-stimulated, LUBAC-catalysed formation of linear ubiquitin chains and their interaction with the NEMO component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKβ at Ser177 and IKKα at Ser176. These findings may be of general significance for the activation of other protein kinases.
    Biochemical Journal 06/2014; DOI:10.1042/BJ20140444 · 4.78 Impact Factor
  • Philip Cohen
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    ABSTRACT: The signaling networks that control the immune system are coordinated by a myriad of interconnecting phosphorylation and ubiquitylation events. This review provides an overview of mutations in human genes encoding these proteins that give rise to immune diseases. Analysis of the biological effects of these mutations has revealed the true physiological roles of particular signaling networks and promises to revolutionize the treatment of these diseases.
    Nature Immunology 05/2014; 15(6):521-9. DOI:10.1038/ni.2892 · 24.97 Impact Factor
  • Philip Cohen
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    ABSTRACT: Toll-like receptors (TLRs) and the receptors for interleukin (IL)-1, IL-18 and IL-33 are required for defence against microbial pathogens but, if hyper-activated or not switched off efficiently, can cause tissue damage and inflammatory and autoimmune diseases. Understanding how the checks and balances in the system are integrated to fight infection without the network operating out of control will be crucial for the development of improved drugs to treat these diseases in the future. In this Cell Science at a Glance article and the accompanying poster, I provide a brief overview of how one of these intricate networks is controlled by the interplay of protein phosphorylation and protein ubiquitylation events, and the mechanisms in myeloid cells that restrict and terminate its activation to prevent inflammatory and autoimmune diseases. Finally, I suggest a few protein kinases that have been neglected as drug targets, but whose therapeutic potential should be explored in the light of recent advances in our understanding of their roles in the innate immune system.
    Journal of Cell Science 05/2014; 127(11). DOI:10.1242/jcs.149831 · 5.33 Impact Factor
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    ABSTRACT: Pathogenic infections and tissue injuries trigger the assembly of inflammasomes, cytosolic protein complexes that activate caspase-1, leading to cleavage of pro-IL-1β and pro-IL-18 and to pyroptosis, a proinflammatory cell death program. Although microbial recognition by Toll-like receptors (TLRs) is known to induce the synthesis of the major caspase-1 substrate pro-IL-1β, the role of TLRs has been considered limited to up-regulation of the inflammasome components. During infection with a virulent microbe, TLRs and nucleotide-binding oligomerization domain-like receptors (NLRs) are likely activated simultaneously. To examine the requirements and outcomes of combined activation, we stimulated TLRs and a specific NLR, nucleotide binding and oligomerization, leucine-rich repeat, pyrin domain-containing 3 (NLRP3), simultaneously and discovered that such activation triggers rapid caspase-1 cleavage, leading to secretion of presynthesized inflammatory molecules and pyroptosis. This acute caspase-1 activation is independent of new protein synthesis and depends on the TLR-signaling molecule IL-1 receptor-associated kinase (IRAK-1) and its kinase activity. Importantly, Listeria monocytogenes induces NLRP3-dependent rapid caspase-1 activation and pyroptosis, both of which are compromised in IRAK-1-deficient macrophages. Our results reveal that simultaneous sensing of microbial ligands and virulence factors by TLRs and NLRP3, respectively, leads to a rapid TLR- and IRAK-1-dependent assembly of the NLRP3 inflammasome complex, and that such activation is important for release of alarmins, pyroptosis, and early IFN-γ production by memory CD8 T cells, all of which could be critical for early host defense.
    Proceedings of the National Academy of Sciences 12/2013; 111(2). DOI:10.1073/pnas.1320294111 · 9.81 Impact Factor
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    ABSTRACT: Research over the past decade has revealed how NF-κB essential modulator (NEMO; also known as IKKγ) regulates the IKKα-IKKβ signalling axis in the innate immune system. The discovery that NEMO is a polyubiquitin-binding protein and that the IKK complex is modulated by other protein kinases that are themselves controlled by polyubiquitin chains has provided a deeper molecular understanding of the non-degradative roles of ubiquitylation. New mechanistic insights of NEMO and related polyubiquitin-binding proteins have become a paradigm for how the interplay between phosphorylation and ubiquitylation controls cell signalling networks in health and disease.
    Nature Reviews Molecular Cell Biology 08/2013; DOI:10.1038/nrm3644 · 36.46 Impact Factor
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    ABSTRACT: Polyubiquitin (pUb) chains formed between the C terminus of ubiquitin and lysine 63 (K63) or methionine 1 (M1) of another ubiquitin have been implicated in the activation of the canonical IκB kinase (IKK) complex. Here, we demonstrate that nearly all of the M1-pUb chains formed in response to interleukin-1, or the Toll-Like Receptors 1/2 agonist Pam3CSK4, are covalently attached to K63-pUb chains either directly as K63-pUb/M1-pUb hybrids or indirectly by attachment to the same protein. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK) 1 is modified first by K63-pUb chains to which M1-pUb linkages are added subsequently, and myeloid differentiation primary response gene 88 (MyD88) and IRAK4 are also modified by both K63-pUb and M1-pUb chains. We show that the heme-oxidized IRP2 ubiquitin ligase 1 interacting protein (HOIP) component of the linear ubiquitin assembly complex catalyzes the formation of M1-pUb chains in response to interleukin-1, that the formation of K63-pUb chains is a prerequisite for the formation of M1-pUb chains, and that HOIP interacts with K63-pUb but not M1-pUb linkages. These findings identify K63-Ub oligomers as a major substrate of HOIP in cells where the MyD88-dependent signaling network is activated. The TGF-beta-activated kinase 1 (TAK1)-binding protein (TAB) 2 and TAB3 components of the TAK1 complex and the NFκB Essential Modifier (NEMO) component of the canonical IKK complex bind to K63-pUb chains and M1-pUb chains, respectively. The formation of K63/M1-pUb hybrids may therefore provide an elegant mechanism for colocalizing both complexes to the same pUb chain, facilitating the TAK1-catalyzed activation of IKKα and IKKβ. Our study may help to resolve the debate about the relative importance of K63-pUb and M1-pUb chains in activating the canonical IKK complex.
    Proceedings of the National Academy of Sciences 08/2013; DOI:10.1073/pnas.1314715110 · 9.81 Impact Factor
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    ABSTRACT: The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-κB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-κB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-κB and mitogen-activated protein kinase activity.
    Journal of the American Society of Nephrology 08/2013; DOI:10.1681/ASN.2013020148 · 9.47 Impact Factor
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    ABSTRACT: The roles of IL-1R-associated kinase (IRAK)2 and IRAK1 in cytokine production were investigated using immune cells from knock-in mice expressing the TNFR-associated factor 6 (TRAF6) binding-defective mutant IRAK2[E525A] or the catalytically inactive IRAK1[D359A] mutant. In bone marrow-derived macrophages (BMDMs), the IRAK2-TRAF6 interaction was required for the late (2-8 h) but not the early phase (0-2 h) of il6 and tnfa mRNA production, and hence for IL-6 and TNF-α secretion by TLR agonists that signal via MyD88. Loss of the IRAK2-TRAF6 interaction had little effect on the MyD88-dependent production of anti-inflammatory molecules produced during the early phase, such as Dual Specificity Phosphatase 1, and a modest effect on IL-10 secretion. The LPS/TLR4-stimulated production of il6 and tnfa mRNA and IL-6 and TNF-α secretion was hardly affected, because the Toll/IL-1R domain-containing adapter-inducing IFN-β (TRIF) signaling pathway was used instead of the IRAK2-TRAF6 interaction to sustain late-phase mRNA production. IRAK1 catalytic activity was not rate limiting for il6, tnfa, or il10 mRNA production or the secretion of these cytokines by BMDMs, but IFN-β mRNA induction by TLR7 and TLR9 agonists was greatly delayed in plasmacytoid dendritic cells (pDCs) from IRAK1[D359A] mice. In contrast, IFN-β mRNA production was little affected in pDCs from IRAK2[E525A] mice, but subsequent IFN-α mRNA production and IFN-α secretion were reduced. IFN-β and IFN-α production were abolished in pDCs from IRAK1[D359A] × IRAK2[E525A] double knock-in mice. Our results establish that the IRAK2-TRAF6 interaction is rate limiting for the late, but not the early phase of cytokine production in BMDM and pDCs, and that the IRAK2-TRAF6 interaction is needed to sustain IκB-inducing kinase β activity during prolonged activation of the MyD88 signaling.
    The Journal of Immunology 08/2013; 191(5). DOI:10.4049/jimmunol.1203268 · 5.36 Impact Factor
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    ABSTRACT: Double-stranded (ds) RNA of viral origin, a ligand for Melanoma Differentiation Associated gene 5 (MDA5) and Toll-Like Receptor 3 (TLR3), induces the TANK-Binding Kinase 1 (TBK1) -dependent phosphorylation and activation of Interferon Regulatory Factor 3 (IRF3) and the E3 ubiquitin ligase Pellino1, which are required for interferon β (IFNβ) gene transcription. Here, we report that Pellino1 interacts with the transcription factor Deformed Epidermal Autoregulatory Factor 1 (DEAF1) The interaction is independent of the E3 ligase activity of Pellino1, but weakened by the phosphorylation of Pellino1. We show that DEAF1 binds to the IFNβ promoter and to IRF3 and IRF7, that it is required for the transcription of the IFNβ gene and IFNβ secretion in MEFs infected with Sendai virus or transfected with poly(I:C). DEAF1 is also needed for TLR3-dependent IFNβ production. Taken together, our results identify DEAF1 as a novel component of the signal transduction network by which dsRNA of viral origin stimulates IFNβ production.
    Journal of Biological Chemistry 07/2013; DOI:10.1074/jbc.M113.479550 · 4.60 Impact Factor
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    ABSTRACT: The compound BAY 11-7082 inhibits IκBα phosphorylation in cells and has been used to implicate the canonical IκB kinases (IKKs) and NFκB in <350 publications. Here we report that BAY 11-7082 does not inhibit the IKKs but suppresses their activation in LPS-stimulated RAW macrophages and IL-1-stimulated IL-1R HEK293 cells. BAY 11-7082 exerts these effects by inactivating the E2 conjugating enzymes Ubc13 and UbcH7 and the E3 ligase LUBAC (linear ubiquitin assembly complex), thereby preventing the formation of Lys63-linked and linear-polyubiquitin chains. BAY 11-7082 prevents ubiquitin conjugation to Ubc13 and UbcH7 by forming a covalent adduct with their reactive cysteine residues via Michael addition at the C3 atom of BAY 11-7082, followed by the release of 4-methylbenzene-sulphinic acid. BAY 11-7082 stimulated Lys48-linked polyubiquitin chain formation in cells and protected HIF1a (hypoxia-inducible factor 1a) from proteasomal degradation, suggesting that it inhibits the proteasome. Our results indicate that the anti-inflammatory effects of BAY 11-7082, its ability to induce B cell lymphoma and leukaemic T cell death and to prevent the recruitment of proteins to sites of DNA damage are exerted via inhibition of components the ubiquitin system and not by inhibiting NFκB.
    Biochemical Journal 02/2013; 451(Pt 3). DOI:10.1042/BJ20121651 · 4.78 Impact Factor
  • Philip Cohen, Dario R. Alessi
    ACS Chemical Biology 02/2013; 8(2):464–464. DOI:10.1021/cb400055x · 5.36 Impact Factor
  • Philip Cohen, Dario R Alessi
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    ABSTRACT: Over the past 15 years protein kinases have become the pharmaceutical industry's most important class of drug target in the field of cancer. Some 20 drugs that target kinases have been approved for clinical use over the past decade, and hundreds more are undergoing clinical trials. However, the recent approval of the first protein kinase inhibitors for the treatment of inflammatory diseases, coupled with an enhanced understanding of the signaling networks that control the immune system, suggests that there will be a surge of interest in this area over the next 10 years. In this connection, we discuss opportunities for targeting protein kinases in the MyD88 signaling network for the development of drugs to treat chronic inflammatory and autoimmune diseases. Activating mutations in protein kinases underlie many other diseases and conditions, and we also discuss why the protein kinases SPAK/OSR1 and LRRK2 have recently become interesting targets for the treatment of hypertension and Parkinson's disease, respectively, and the progress that has been made in developing LRRK2 inhibitors. Finally we suggest that more focus on the identification of inhibitors of kinase activation, rather than kinase activity, may pay dividends in identifying exquisitely specific inhibitors of signal transduction cascades, and we also highlight "pseudo-kinases" as an attractive and unexplored area for drug development that merits much more attention in the years to come.
    ACS Chemical Biology 12/2012; 8(1). DOI:10.1021/cb300610s · 5.36 Impact Factor
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    ABSTRACT: Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases.
    Proceedings of the National Academy of Sciences 10/2012; 109(42):16986-16991. DOI:10.1073/pnas.1215450109 · 9.81 Impact Factor
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    ABSTRACT: The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.
    Bioorganic & medicinal chemistry letters 09/2012; 22(23). DOI:10.1016/j.bmcl.2012.09.063 · 2.33 Impact Factor
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    ABSTRACT: Viral double-stranded RNA, a ligand for Toll-like Receptor 3 (TLR3) and the cytoplasmic RNA receptors RIG1 and MDA5, activate a signaling network in which the IKK-related protein kinase TBK1 phosphorylates the transcription factor Interferon Regulatory Factor 3 (IRF3) and the E3 ubiquitin ligase Pellino1. IRF3 then translocates to the nucleus where it stimulates transcription of the interferonβ (IFNβ) gene, but the function of Pellino1 in this pathway is unknown. Here, we report that myeloid cells and embryonic fibroblasts from knock-in mice expressing an E3 ligase-deficient mutant of Pellino1 produce reduced levels of IFNβ mRNA and secrete much less IFNβ in response to viral double-stranded RNA because the interaction of IRF3 with the IFNβ promoter is impaired. These results identify Pellino1 as a novel component of the signal transduction network by which viral double-stranded RNA stimulates IFNβ gene transcription.
    Journal of Biological Chemistry 08/2012; 287(41):34825-35. DOI:10.1074/jbc.M112.367557 · 4.60 Impact Factor

Publication Stats

9k Citations
773.93 Total Impact Points

Institutions

  • 1992–2015
    • University of Dundee
      • • MRC Protein Phosphorylation Unit
      • • College of Life Sciences
      Dundee, Scotland, United Kingdom
  • 2005
    • University of Tuebingen
      • Institute for Physiology
      Tübingen, Baden-Württemberg, Germany
  • 2003
    • University of Greifswald
      • Institute of Pathology
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 2002
    • University of Helsinki
      Helsinki, Uusimaa, Finland
    • University of Bergen
      • Department of Biomedicine
      Bergen, Hordaland, Norway