Mendoza, H. et al. Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. Biochem. J. 409, 711-722

MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, UK.
Biochemical Journal (Impact Factor: 4.4). 03/2008; 409(3):711-22. DOI: 10.1042/BJ20071149
Source: PubMed

ABSTRACT The protein kinase TAK1 (transforming growth factor-beta-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 p38alpha MAPK down-regulates TAK1 and showed that p38alpha MAPK phosphorylates TAB1 at Ser(423) and Thr(431). In the present study, we identified two IL-1-stimulated phosphorylation sites on TAB2 (Ser(372) and Ser(524)) and three on TAB3 (Ser(60), Thr(404) and Ser(506)) in human IL-1R cells [HEK-293 (human embryonic kidney) cells that stably express the IL-1 receptor] and MEFs (mouse embryonic fibroblasts). Ser(372) and Ser(524) of TAB2 are not phosphorylated by pathways dependent on p38alpha/beta MAPKs, ERK1/2 (extracellular-signal-regulated kinase 1/2) and JNK1/2 (c-Jun N-terminal kinase 1/2). In contrast, Ser(60) and Thr(404) of TAB3 appear to be phosphorylated directly by p38alpha MAPK, whereas Ser(506) is phosphorylated by MAPKAP-K2/MAPKAP-K3 (MAPK-activated protein kinase 2 and 3), which are protein kinases activated by p38alpha MAPK. Studies using TAB1(-/-) MEFs indicate important roles for TAB1 in recruiting p38alpha MAPK to the TAK1 complex for the phosphorylation of TAB3 at Ser(60) and Thr(404) and in inhibiting the dephosphorylation of TAB3 at Ser(506). TAB1 is also required to induce TAK1 catalytic activity, since neither IL-1 nor TNFalpha was able to stimulate detectable TAK1 activity in TAB1(-/-) MEFs. Surprisingly, the IL-1 and TNFalpha-stimulated activation of MAPK cascades and IkappaB (inhibitor of nuclear factor kappaB) 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/TNFalpha-induced activation of these signalling pathways in TAB1(-/-) and MEKK3(-/-) MEFs.

Download full-text


Available from: James Hastie, Sep 08, 2015
1 Follower
27 Reads
  • Source
    • "MyD88 then triggers the activation of a multi-step cascade of IL-1 receptor-associated kinase 4 (IRAK4), IRAK1 and tumor necrosis factor receptor-associated factor 6 (TRAF6) activation (Hopkins and Sriskandan, 2005; Takeda and Akira, 2004b). The activated IRAK1/TRAF6 complex disassociates from the receptor complex and further activates the downstream TGF-b-activated kinase-1 (TAK1) kinase complex (Besse et al., 2007; Mendoza et al., 2008). The TAK1 complex then phosphorylates and activates IkB kinase (IKK), which leads to the activation of Contents lists available at ScienceDirect "
    [Show abstract] [Hide abstract]
    ABSTRACT: Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) is a multifunctional adaptor protein that plays a key role in the regulation of the oxidative phosphorylation (OXPHOS) system, bone morphogenetic protein (BMP) pathway and Toll-like receptor (TLR) signaling pathway in mammals. However, the function of ECSIT homologs in mollusks, the second most diverse group of animals, is not well understood. In this study, we identified an ECSIT homolog in the Hong Kong oyster Crassostrea hongkongensis (ChECSIT) and investigated its biological functions. The full-length cDNA of ChECSIT is 1,734 bp and includes an open reading frame (ORF) of 1,074 bp that encodes a polypeptide of 451 amino acids. The predicted ChECSIT protein shares similar structural characteristics with other known ECSIT family proteins. Quantitative real-time PCR analysis revealed that ChECSIT mRNA is broadly expressed in all of the examined tissues and at different stages of embryonic development; its transcript level could be significantly up-regulated by challenge with microorganisms (Vibrio alginolyticus, Staphylococcus haemolyticus and Saccharomyces cerevisiae). In addition, ChECSIT was found to be located primarily in the cytoplasm, and its overexpression stimulated the transcriptional activity of an NF-κB reporter gene in HEK293T cells. These findings suggest that ChECSIT might be involved in embryogenesis processes and immune responses in C. hongkongensis. Copyright © 2015. Published by Elsevier Ltd.
    Developmental and comparative immunology 07/2015; 53(1). DOI:10.1016/j.dci.2015.07.015 · 2.82 Impact Factor
  • Source
    • "The engagement of TLR ectodomains by cognate ligands causes the recruitment of TIR-domain-containing adaptor molecule MyD88 to the cytoplasmic TIR domains of TLRs expect TLR3, leading to successive activation of IL-1 receptor-associated kinase 4 (IRAK4), IRAK1, and tumor necrosis factor receptor-associated factor 6 (TRAF6) Akira et al., 2001; Blasius and Beutler, 2010; Besse et al., 2007. The activated IRAK1/TRAF6 complex disassociates from the receptor complex and interacts with another complex consisting of transforming growth factor (TGF)-b activated kinase 1 (TAK1) and TAK1-binding protein (TAB)1, TAB2 and TAB3 (Besse et al., 2007; Mendoza et al., 2008). Pellino, a highly conserved E3 class ubiquitin ligase in both vertebrates and invertebrates, is an upstream mediator in the TLR pathway (Moynagh, 2009; Schauvliege et al., 2006, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pellino, named after its property that binds Pelle (the Drosophila melanogaster homologue of IRAK1), is a highly conserved E3 class ubiquitin ligase in both vertebrates and invertebrates. Pellino interacts with phosphorylated IRAK1, causing polyubiquitination of IRAK1, and plays a critical upstream role in the toll-like receptor (TLR) pathway. In this study, we firstly cloned and identified a crustacean Pellino from pacific white shrimp Litopenaeus vannamei (LvPellino). LvPellino contains a putative N-terminal forkhead-associated (FHA) domain and a C-terminal ring finger (RING) domain with a potential E3 ubiquitin-protein ligase activity, and shows a high similarity with D. melanogaster Pellino. LvPellino could interact with L. vannamei Pelle (LvPelle) and over-expression of LvPellino could increase the activity of LvDorsal (a L. vannamei homologue of NF-κB) on promoters containing NF-κB binding motifs and enhance the expression of arthropod antimicrobial peptides (AMPs). The LvPellino protein was located in the cytoplasm and nucleus and LvPellino mRNA was detected in all the tissues examined and could be up-regulated after lipopolysaccharides, white spot syndrome virus (WSSV), Vibrio parahaemolyticus, and Staphylococcus aureus challenges, suggesting a stimulation response of LvPellino to bacterial and immune stimulant challenges. Knockdown of LvPellino in vivo could significantly decrease the expression of AMPs and increase the mortality of shrimps caused by V. parahaemolyticus challenge. However, suppression of the LvPellino expression could not change the mortality caused by WSSV infection, and dual-luciferase reporter assays demonstrated that over-expression of LvPellino could enhance the promoters of WSSV genes wsv069 (ie1), wsv303, and wsv371, indicating a complex role of LvPellino in WSSV pathogenesis and shrimp antiviral mechanisms.
    Developmental and comparative immunology 01/2014; 44(2). DOI:10.1016/j.dci.2014.01.012 · 2.82 Impact Factor
  • Source
    • "activity [109] [110] [111] [112] "
    [Show abstract] [Hide abstract]
    ABSTRACT: The p38 mitogen-activated protein kinase (MAPK) signaling pathway has been strongly implicated in many of the processes that underlie the pathology of rheumatoid arthritis (RA). For many years it has been considered a promising target for development of new anti-inflammatory drugs with which to treat RA and other chronic immune-mediated inflammatory diseases. However, several recent clinical trials have concluded in a disappointing manner. Why is this so, if p38 MAPK clearly contributes to the excessive production of inflammatory mediators, the destruction of bone and cartilage? We argue that, to explain the apparent failure of p38 inhibitors in the rheumatology clinic, we need to understand better the complexities of the p38 pathway and its many levels of communication with other cellular signaling pathways. In this review we look at the p38 MAPK pathway from a slightly different perspective, emphasising its role in post-transcriptional rather than transcriptional control of gene expression, and its contribution to the off-phase rather than the on-phase of the inflammatory response.
    The Open Rheumatology Journal 09/2012; 6(1):209-219. DOI:10.2174/1874312901206010209
Show more