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  • Portland Press Ltd.  (5)
  • English  (5)
  • 1
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    TPL2 meets p38MAPK: emergence of a novel positive feedback loop in inflammation
    Portland Press Ltd. ; 2016
    In:  Biochemical Journal Vol. 473, No. 19 ( 2016-10-01), p. 2995-2999
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 473, No. 19 ( 2016-10-01), p. 2995-2999
    Abstract: The activation of p38MAPK by Toll-like receptor signalling is essential for the inflammatory response of innate immunity due to its role in post-transcriptional regulation of TNFα and cytokine biosynthesis. p38MAPK activation proceeds by the upstream MAP2Ks, MAPK kinase (MKK)3/6 as well as MKK4, which in turn are substrates for MAP3Ks, such as TGFβ-activated protein kinase-1 (TAK1). In contrast, TPL2 has been described as an exclusive MAP3K of MKK1/2-triggering activation of the classical ERKs, ERK1/2. In the recent issue of the Biochemical Journal, Pattison et al. report their screening for TPL2 substrates in LPS-stimulated macrophages and the identification of MKK3/6. Using catalytic-dead TPL2 (Map3k8D270A/D270A) knockin macrophages, they demonstrated that activation of MKK3/6 by TPL2 significantly contributes to LPS-dependent TNFα biosynthesis and is also essential for TNF-receptor 1 signalling. Hence, a new signalling pathway from TAK1 via IκB kinase, p105 NFκB and TPL2 to MKK3/6 and p38MAPK is established in macrophages. Taking into account that some isoforms of p38MAPK are necessary for maintaining functional steady-state levels of TPL2, a positive feedback loop in inflammation emerges.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BCJ20160672C
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2016
    detail.hit.zdb_id: 1473095-9
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  • 2
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    Molecular mechanisms of phosphorylation-regulated TTP (tristetraprolin) action and screening for further TTP-interacting proteins
    Portland Press Ltd. ; 2010
    In:  Biochemical Society Transactions Vol. 38, No. 6 ( 2010-12-01), p. 1632-1637
    Details
    In: Biochemical Society Transactions, Portland Press Ltd., Vol. 38, No. 6 ( 2010-12-01), p. 1632-1637
    Abstract: TTP (tristetraprolin) is an RNA-binding protein which regulates mRNA stability or translation or both. The molecular mechanisms which are responsible and which discriminate between regulation of mRNA stability and translation are not completely understood so far, but are clearly dependent on p38 MAPK (mitogen-activated protein kinase)/MK (MAPK-activated protein kinase) 2/3-mediated phosphorylation of TTP. To learn more about these mechanisms, phosphorylation-dependent TTP-interacting proteins could be of great interest. Many interacting partners, which belong to the mRNA-processing and -regulating machinery, have been identified by hypothesis-driven co-immunoprecipitation and in the classical Y2H (yeast two-hybrid) approach, where TTP was identified as prey, and are summarized in the present paper. However, because of transactivating properties of TTP, an unbiased Y2H approach using TTP as bait was hindered. Since novel methods for the identification of phosphorylation-dependent interaction partners and of interactors of full-length auto-activating proteins in eukaryotic systems have evolved in the last few years, these methods should be applied to screen for additional phosphorylation-dependent interaction partners of TTP and could lead towards a complete understanding of TTP function at the molecular level.
    Type of Medium: Online Resource
    ISSN: 0300-5127 , 1470-8752
    URL: Article
    DOI: 10.1042/BST0381632
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2010
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  • 3
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    Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex
    Portland Press Ltd. ; 2008
    In:  Biochemical Journal Vol. 409, No. 3 ( 2008-02-01), p. 711-722
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 409, No. 3 ( 2008-02-01), p. 711-722
    Abstract: The protein kinase TAK1 (transforming growth factor-β-activated kinase 1), which has been implicated in the activation of MAPK (mitogen-activated protein kinase) cascades and the production of inflammatory mediators by LPS (lipopolysaccharide), IL-1 (interleukin 1) and TNF (tumour necrosis factor), comprises the catalytic subunit complexed to the regulatory subunits, termed TAB (TAK1-binding subunit) 1 and either TAB2 or TAB3. We have previously identified a feedback-control mechanism by which p38α MAPK down-regulates TAK1 and showed that p38α MAPK phosphorylates TAB1 at Ser423 and Thr431. In the present study, we identified two IL-1-stimulated phosphorylation sites on TAB2 (Ser372 and Ser524) and three on TAB3 (Ser60, Thr404 and Ser506) in human IL-1R cells [HEK-293 (human embryonic kidney) cells that stably express the IL-1 receptor] and MEFs (mouse embryonic fibroblasts). Ser372 and Ser524 of TAB2 are not phosphorylated by pathways dependent on p38α/β MAPKs, ERK1/2 (extracellular-signal-regulated kinase 1/2) and JNK1/2 (c-Jun N-terminal kinase 1/2). In contrast, Ser60 and Thr404 of TAB3 appear to be phosphorylated directly by p38α MAPK, whereas Ser506 is phosphorylated by MAPKAP-K2/MAPKAP-K3 (MAPK-activated protein kinase 2 and 3), which are protein kinases activated by p38α MAPK. Studies using TAB1−/− MEFs indicate important roles for TAB1 in recruiting p38α MAPK to the TAK1 complex for the phosphorylation of TAB3 at Ser60 and Thr404 and in inhibiting the dephosphorylation of TAB3 at Ser506. TAB1 is also required to induce TAK1 catalytic activity, since neither IL-1 nor TNFα was able to stimulate detectable TAK1 activity in TAB1−/− MEFs. Surprisingly, the IL-1 and TNFα-stimulated activation of MAPK cascades and IκB (inhibitor of nuclear factor κB) kinases were similar in TAB1−/−, MEKK3−/− [MAPK/ERK (extracellular-signal-regulated kinase) kinase kinase 3] and wild-type MEFs, suggesting that another MAP3K (MAPK kinase kinase) may mediate the IL-1/TNFα-induced activation of these signalling pathways in TAB1−/− and MEKK3−/− MEFs.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20071149
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2008
    detail.hit.zdb_id: 1473095-9
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  • 4
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    Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production
    Portland Press Ltd. ; 2013
    In:  Biochemical Journal Vol. 456, No. 2 ( 2013-12-01), p. 163-172
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 456, No. 2 ( 2013-12-01), p. 163-172
    Abstract: The p38 MAPK (mitogen-activated protein kinase)/MK2 [MAPKAP (MAPK-activated protein) kinase-2] signalling pathway is a major regulator of stress- and cytokine-induced gene expression at the transcriptional and post-transcriptional level. Using phosphoproteomics we identified the ER (endoplasmic reticulum)-associated ubiquitin-conjugating enzyme Ube2j1 as a potential substrate of MK2. We demonstrate that Ube2j1 is phosphorylated in a cytokine-, cytosolic stress- and LPS (lipopolysaccharide)-induced manner. The cytosolic stress-induced phosphorylation of Ube2j1 proceeds at Ser184, a site described previously to be phosphorylated in response to ER stress, which is located in a perfect MK2 consensus motif. The cytosolic stress-induced phosphorylation of Ube2j1, but not its ER-stress-induced phosphorylation is sensitive to p38/MK2 inhibitors and abrogated in MK2/MK3-deficient cells. In a pull-down assay we demonstrate the interaction of MK2 with Ube2j1 in HEK (human embryonic kidney)-293T cells. Furthermore, MK2 is able to phosphorylate recombinant Ube2j1, but not the S184A mutant in an in vitro kinase assay. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser184 upon p38-activating stress in vivo. However, ectopically expressed Ube2j1-S184A mutant displays ubiquitinating activity towards the model substrate ER-synthesized T-cell receptor-α similar to that of the wild-type protein. Interestingly, Ube2j1 is phosphorylated in response to LPS also in macrophages and contributes to MK2-dependent TNFα biosynthesis by a so far unknown mechanism.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20130755
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2013
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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  • 5
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    Monitoring protein–protein interactions in mammalian cells by trans -SUMOylation
    Portland Press Ltd. ; 2011
    In:  Biochemical Journal Vol. 438, No. 3 ( 2011-09-15), p. 495-503
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 438, No. 3 ( 2011-09-15), p. 495-503
    Abstract: Protein–protein interactions are essential for almost all cellular processes, hence understanding these processes mainly depends on the identification and characterization of the relevant protein–protein interactions. In the present paper, we introduce the concept of TRS (trans-SUMOylation), a new method developed to identify and verify protein–protein interactions in mammalian cells in vivo. TRS utilizes Ubc9-fusion proteins that trans-SUMOylate co-expressed interacting proteins. Using TRS, we analysed interactions of 65 protein pairs co-expressed in HEK (human embryonic kidney)-293 cells. We identified seven new and confirmed 16 known protein interactions, which were determined via endogenous SUMOylation sites of the binding partners or by using SUMOylation-site tags respectively. Four of the new protein interactions were confirmed by GST (glutathione transferase) pull-down and the p38α–Edr2 interaction was verified by co-localization analysis. Functionally, this p38α–Edr2 interaction could possibly be involved in the recruitment of p38α to the polycomb chromatin-remodelling complex to phosphorylate Bmi1. We also used TRS to characterize protein-interaction domains of the protein kinase pairs p38α–MK2 [MK is MAPK (mitogen-activated protein kinase)-activated protein kinase] and ERK3 (extracellular-signal-regulated kinase 3)–MK5 and of the p38α–p53 complex. The ability of TRS to monitor protein interactions in mammalian cells in vivo at levels similar to endogenous expression makes it an excellent new tool that can help in defining the protein interactome of mammalian cells.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20110035
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2011
    detail.hit.zdb_id: 1473095-9
    SSG: 12
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