Genomes and Genes
map kinase kinase kinases
Summary: Mitogen-activated protein kinase kinase kinases (MAPKKKs) are serine-threonine protein kinases that initiate protein kinase signaling cascades. They phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES; (MAPKKs) which in turn phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs).
- Xiong X, Hao Y, Sun K, Li J, Li X, Mishra B, et al. The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein. PLoS Biol. 2012;10:e1001440 pubmed publisher..Through independent regulation of Wnd/DLK, whose function is required for proximal axons to regenerate, Hiw plays a central role in coordinating both regenerative and degenerative responses to axonal injury...
- Ori D, Kato H, Sanjo H, Tartey S, Mino T, Akira S, et al. Essential roles of K63-linked polyubiquitin-binding proteins TAB2 and TAB3 in B cell activation via MAPKs. J Immunol. 2013;190:4037-45 pubmed publisher..Thus, TAB2- and TAB3-mediated K63-linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1/NF-?B axis. ..
- Lamothe B, Lai Y, Xie M, Schneider M, Darnay B. TAK1 is essential for osteoclast differentiation and is an important modulator of cell death by apoptosis and necroptosis. Mol Cell Biol. 2013;33:582-95 pubmed publisher..To our knowledge, we are the first to report that mice in which TAK1 has been conditionally deleted in osteoclasts develop osteopetrosis. ..
- Sharma M, Gadang V, Jaeschke A. Critical role for mixed-lineage kinase 3 in acetaminophen-induced hepatotoxicity. Mol Pharmacol. 2012;82:1001-7 pubmed publisher..Together, these studies establish a novel role for MLK3 in APAP-induced JNK activation and hepatotoxicity, and they suggest MLK3 as a possible target in the treatment of APAP-induced liver injury. ..
- Zalatan J, Coyle S, Rajan S, Sidhu S, Lim W. Conformational control of the Ste5 scaffold protein insulates against MAP kinase misactivation. Science. 2012;337:1218-22 pubmed publisher..Thus, in addition to serving as a conduit guiding kinase communication, Ste5 directly receives input information to decide if and when signal can be transmitted to mating output. ..
- Huntwork Rodriguez S, Wang B, Watkins T, Ghosh A, Pozniak C, Bustos D, et al. JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis. J Cell Biol. 2013;202:747-63 pubmed publisher..Through this feedback mechanism, the ubiquitin-proteasome system is able to provide an additional layer of regulation of retrograde stress signaling to generate a global cellular response to localized external insults. ..
- Dondelinger Y, Aguileta M, Goossens V, Dubuisson C, Grootjans S, Dejardin E, et al. RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death Differ. 2013;20:1381-92 pubmed publisher..In contrast, RIPK3 participates in caspase-8 activation by acting downstream of the cytosolic death complex assembly, possibly via reactive oxygen species generation. ..
- Yang H, Papoutsopoulou S, Belich M, Brender C, Janzen J, Gantke T, et al. Coordinate regulation of TPL-2 and NF-?B signaling in macrophages by NF-?B1 p105. Mol Cell Biol. 2012;32:3438-51 pubmed publisher..Unexpectedly, TPL-2 promoted soluble TNF production independently of IKK-induced p105 phosphorylation and its ability to activate ERK, which has important implications for the development of anti-inflammatory drugs targeting TPL-2. ..
- Humphrey R, Yu S, Bellary A, Gonuguntla S, Yebra M, Jhala U. Lysine 63-linked ubiquitination modulates mixed lineage kinase-3 interaction with JIP1 scaffold protein in cytokine-induced pancreatic ? cell death. J Biol Chem. 2013;288:2428-40 pubmed publisher..These studies suggest a novel mechanism for MLK3 activation and provide new clues for therapeutic intervention in promoting ? cell survival. ..
- Cao X, Yue L, Song J, Wu Q, Li N, Luo L, et al. Inducible HSP70 antagonizes IL-1? cytocidal effects through inhibiting NF-kB activation via destabilizing TAK1 in HeLa cells. PLoS ONE. 2012;7:e50059 pubmed publisher..This research also provides insight into mechanisms by which HSP70 exerts its cytoprotective action upon toxic stimuli in tumor cells. ..
- Yumoto K, Thomas P, Lane J, Matsuzaki K, Inagaki M, Ninomiya Tsuji J, et al. TGF-?-activated kinase 1 (Tak1) mediates agonist-induced Smad activation and linker region phosphorylation in embryonic craniofacial neural crest-derived cells. J Biol Chem. 2013;288:13467-80 pubmed publisher..The role of Smad-independent TGF-? signaling in craniofacial development is poorly elucidated...
- Watkins T, Wang B, Huntwork Rodriguez S, Yang J, Jiang Z, Eastham Anderson J, et al. DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc Natl Acad Sci U S A. 2013;110:4039-44 pubmed publisher..These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism...
- Dai L, Aye Thu C, Liu X, Xi J, Cheung P. TAK1, more than just innate immunity. IUBMB Life. 2012;64:825-34 pubmed publisher..This review will focus on recent developments and also examine the regulation of TAK1 in response to a diverse range of other stimuli including DNA damage, transforming growth factor-?, Wnt, osmotic stress, and hypoxia. ..
- Emmerich C, Ordureau A, Strickson S, Arthur J, Pedrioli P, Komander D, et al. Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc Natl Acad Sci U S A. 2013;110:15247-52 pubmed publisher..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. ..
- Martinez García M, Banerji U, Albanell J, Bahleda R, Dolly S, Kraeber Bodéré F, et al. First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors. Clin Cancer Res. 2012;18:4806-19 pubmed
- Hashimoto M, Komatsu K, Maejima K, Okano Y, Shiraishi T, Ishikawa K, et al. Identification of three MAPKKKs forming a linear signaling pathway leading to programmed cell death in Nicotiana benthamiana. BMC Plant Biol. 2012;12:103 pubmed publisher..Furthermore, these three MAPKKKs form a linear signaling pathway leading to PCD; this pathway proceeds from NbMAPKKK? to NbMAPKKK? to NbMAPKKK?. ..
- Pera T, Sami R, Zaagsma J, Meurs H. TAK1 plays a major role in growth factor-induced phenotypic modulation of airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2011;301:L822-8 pubmed publisher..In addition, LL-Z-1640-2 inhibited PDGF-induced reduction of BTSM contractility and smooth muscle ?-actin expression. The data indicate that TAK1 plays a major role in growth factor-induced phenotypic modulation of ASM. ..
- Lawrenz M, Visekruna A, Kuhl A, Schmidt N, Kaufmann S, Steinhoff U. Genetic and pharmacological targeting of TPL-2 kinase ameliorates experimental colitis: a potential target for the treatment of Crohn's disease?. Mucosal Immunol. 2012;5:129-39 pubmed publisher..Because increased TPL-2/ERK activation was seen in patients with Crohn's disease (CD) but not ulcerative colitis, our findings encourage further investigation of TPL-2 kinase as potential target for the treatment of CD patients. ..
- Wajant H, Scheurich P. TNFR1-induced activation of the classical NF-?B pathway. FEBS J. 2011;278:862-76 pubmed publisher..Here, we sum up the known details of TNFR1-induced IKK activation, address arising contradictions and discuss possible explanations resolving the apparent discrepancies. ..
- Omori E, Matsumoto K, Zhu S, Smart R, Ninomiya Tsuji J. Ablation of TAK1 upregulates reactive oxygen species and selectively kills tumor cells. Cancer Res. 2010;70:8417-25 pubmed publisher..Normal skin did not exhibit any significant abnormality on tak1 gene deletion. Thus, TAK1 kinase could be a new and effective molecular target for ROS-based tumor killing. ..
- Xiong X, Wang X, Ewanek R, Bhat P, DiAntonio A, Collins C. Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury. J Cell Biol. 2010;191:211-23 pubmed publisher..Our data suggest that the regulation of Wnd protein turnover by Hiw can function as a damage surveillance mechanism for responding to axonal injury. ..
- Takahashi Y, Soyano T, Kosetsu K, Sasabe M, Machida Y. HINKEL kinesin, ANP MAPKKKs and MKK6/ANQ MAPKK, which phosphorylates and activates MPK4 MAPK, constitute a pathway that is required for cytokinesis in Arabidopsis thaliana. Plant Cell Physiol. 2010;51:1766-76 pubmed publisher..Although HINKEL/AtNACK1 (HIK) KLP, ANP MAP kinase kinase kinases (MAPKKKs) and MKK6/ ANQ MAP kinase kinase (MAPKK) have been identified independently as regulators of ..
- Wang J, Medress Z, Barres B. Axon degeneration: molecular mechanisms of a self-destruction pathway. J Cell Biol. 2012;196:7-18 pubmed publisher..A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra-axonal calcium levels and calcium-dependent cytoskeletal breakdown. ..
- Xiao Y, Li H, Zhang J, Volk A, Zhang S, Wei W, et al. TNF-?/Fas-RIP-1-induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations. Blood. 2011;118:6057-67 pubmed publisher..Tak1 mediates a critical survival signal, which protects against both TNF-?/Fas-RIP-1-dependent necroptosis and TNF-?/Fas-independent apoptosis in HSPCs. ..
- Bottero V, Kerur N, Sadagopan S, Patel K, Sharma Walia N, Chandran B. Phosphorylation and polyubiquitination of transforming growth factor beta-activated kinase 1 are necessary for activation of NF-kappaB by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. J Virol. 2011;85:1980-93 pubmed publisher..Finally, inhibition of TAK1 by celastrol inhibited vGPCR-induced NF-?B activation, indicating this natural compound could be used as a potential therapeutic drug against KSHV malignancies involving vGPCR...
- Fan Y, Yu Y, Mao R, Zhang H, Yang J. TAK1 Lys-158 but not Lys-209 is required for IL-1?-induced Lys63-linked TAK1 polyubiquitination and IKK/NF-?B activation. Cell Signal. 2011;23:660-5 pubmed publisher..Reconstitution of TAK1-deficient mouse embryo fibroblast cells with wild-type, K158R mutant, or K209R mutant TAK1 reveals that TAK1 Lys-158 but not Lys-209 is required for IL-1?-induced IKK, p38 and JNK activation. ..
- Boyce K, Andrianopoulos A. Ste20-related kinases: effectors of signaling and morphogenesis in fungi. Trends Microbiol. 2011;19:400-10 pubmed publisher..In particular, the importance of PAKs during pathogenesis will be examined. ..
- Ghosh A, Wang B, Pozniak C, Chen M, Watts R, Lewcock J. DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity. J Cell Biol. 2011;194:751-64 pubmed publisher..DLK-null mice displayed reduced apoptosis in multiple neuronal populations during development, demonstrating that prodegenerative DLK signaling is required in vivo. ..
- Li Q, Yan J, Mao A, Li C, Ran Y, Shu H, et al. Tripartite motif 8 (TRIM8) modulates TNF?- and IL-1?-triggered NF-?B activation by targeting TAK1 for K63-linked polyubiquitination. Proc Natl Acad Sci U S A. 2011;108:19341-6 pubmed publisher..Our findings demonstrate that TRIM8 serves as a critical regulator of TNF?- and IL-1?-induced NF-?B activation by mediating K63-linked polyubiquitination of TAK1. ..
- Vanlangenakker N, Vanden Berghe T, Bogaert P, Laukens B, Zobel K, Deshayes K, et al. cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent reactive oxygen species production. Cell Death Differ. 2011;18:656-65 pubmed publisher..In conclusion, our data indicate that cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent ROS production. ..
- Wang Z, Yang Y, Yang H, Capó Aponte J, Tachado S, Wolosin J, et al. NF-?B feedback control of JNK1 activation modulates TRPV1-induced increases in IL-6 and IL-8 release by human corneal epithelial cells. Mol Vis. 2011;17:3137-46 pubmed..Such regulation depends on NF-?B modulation of DUSP1 expression levels and associated changes in PKC? protein levels. ..
- Eftychi C, Karagianni N, Alexiou M, Apostolaki M, Kollias G. Myeloid TAKI [corrected] acts as a negative regulator of the LPS response and mediates resistance to endotoxemia. PLoS ONE. 2012;7:e31550 pubmed publisher..These results highlight an antiinflammatory role for myeloid TAK1, which is essential for balanced innate immune responses and host survival during endotoxemia. ..
- Dong Q, Dougan D, Gong X, Halkowycz P, Jin B, Kanouni T, et al. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett. 2011;21:1315-9 pubmed publisher..Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment. ..
- Sarkar S, Han J, Sinsimer K, Liao B, Foster R, Brewer G, et al. RNA-binding protein AUF1 regulates lipopolysaccharide-induced IL10 expression by activating IkappaB kinase complex in monocytes. Mol Cell Biol. 2011;31:602-15 pubmed publisher..Thus, p40(AUF1) regulates a critical node within the NF-?B signaling pathway to permit IL10 induction for the anti-inflammatory arm of an innate immune response. ..
- Lam C, Tan M, Tan S, Tang M, Cheung P, Tan N. TAK1 regulates SCF expression to modulate PKB? activity that protects keratinocytes from ROS-induced apoptosis. Cell Death Differ. 2011;18:1120-9 pubmed publisher..Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology. ..
- Sayama K, Kajiya K, Sugawara K, Sato S, Hirakawa S, Shirakata Y, et al. Inflammatory mediator TAK1 regulates hair follicle morphogenesis and anagen induction shown by using keratinocyte-specific TAK1-deficient mice. PLoS ONE. 2010;5:e11275 pubmed publisher..These studies provide the first evidence that the inflammatory mediator TAK1 regulates hair follicle induction and morphogenesis, and is required for anagen induction and anagen maintenance. ..
- Strippoli R, Benedicto I, Foronda M, Perez Lozano M, Sánchez Perales S, López Cabrera M, et al. p38 maintains E-cadherin expression by modulating TAK1-NF-kappa B during epithelial-to-mesenchymal transition. J Cell Sci. 2010;123:4321-31 pubmed publisher..This represents a novel role of p38 as a brake or 'gatekeeper' of EMT induction by maintaining E-cadherin levels. ..
- Soria Castro I, Krzyzanowska A, Pelaéz M, Regadera J, Ferrer G, Montoliu L, et al. Cot/tpl2 (MAP3K8) mediates myeloperoxidase activity and hypernociception following peripheral inflammation. J Biol Chem. 2010;285:33805-15 pubmed publisher..In conclusion, our study demonstrates an important role of Cot/tpl2 in the NGF, G-CSF, and GM-CSF production and myeloperoxidase activity in the acute inflammatory response process and its implication in inflammatory hypernociception. ..
- Garlena R, Gonda R, Green A, Pileggi R, Stronach B. Regulation of mixed-lineage kinase activation in JNK-dependent morphogenesis. J Cell Sci. 2010;123:3177-88 pubmed publisher..Finally, expression of various Slpr constructs alone or with upstream activators reveals a wide-ranging response at the cell and tissue level. ..
- Vucur M, Roderburg C, Bettermann K, Tacke F, Heikenwalder M, Trautwein C, et al. Mouse models of hepatocarcinogenesis: what can we learn for the prevention of human hepatocellular carcinoma?. Oncotarget. 2010;1:373-8 pubmed..Molecular findings in this mouse model and their possible significance for chemopreventive strategies against HCC are compared to other murine HCC models. ..
- Melvin A, Mudie S, Rocha S. Further insights into the mechanism of hypoxia-induced NF?B. [corrected]. Cell Cycle. 2011;10:879-82 pubmed..Hypoxia prevents I?B? de-sumoylation of Sumo-2/3 chains on critical lysine residues, normally required for K-48 linked polyubiquitination. Our results define a novel pathway regulating NF?B activation. ..
- Ahmed N, Zeng M, Sinha I, Polin L, Wei W, Rathinam C, et al. The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation. Nat Immunol. 2011;12:1176-83 pubmed publisher..Thus, we have identified an Itch-Cyld-mediated regulatory mechanism in innate inflammatory cells. ..
- Packer L, Rana S, Hayward R, O Hare T, Eide C, Rebocho A, et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell. 2011;20:715-27 pubmed publisher..Thus, we show that imatinib, nilotinib, and dasatinib drive paradoxical RAF/MEK/ERK pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo. ..
- Ajibade A, Wang Q, Cui J, Zou J, Xia X, Wang M, et al. TAK1 negatively regulates NF-?B and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils. Immunity. 2012;36:43-54 pubmed publisher..Our findings identify a previously unrecognized role of TAK1 as a negative regulator of p38 and IKK activation in a cell type-specific manner. ..