Abstract
Transforming growth factor β activated kinase-1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, has emerged as a key regulator of signal transduction cascades leading to the activation of the transcription factors nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). Stimulation of cells with cytokines and microbial pathogens results in the activation of TAK1, which subsequently activates the I-kappa B kinase complex (IKK) and mitogen-activated protein (MAP) kinases, culminating in the activation of NF-κB and AP-1, respectively. Recent studies have shown that polyubiquitination of signalling proteins through lysine (Lys)-63-linked polyubiquitin chains plays an important role in the activation of TAK1 and IKK. Unlike Lys-48-linked polyubiquitination, which normally targets proteins for degradation by the proteasome, Lys-63-linked polyubiquitin chains act as scaffolds to assemble protein kinase complexes and mediate their activation through proteasome-independent mechanisms. The concept of ubiquitin-mediated activation of protein kinases is supported by the discoveries of ubiquitination and deubiquitination enzymes as well as ubiquitin-binding proteins that function upstream of TAK1 and IKK. Recent biochemical and genetic studies provide further insights into the mechanism and function of ubiquitin signalling and these advances will be the focus of this review.
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References
Abbott DW, Wilkins A, Asara JM, Cantley LC . (2004). The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 14: 2217–2227.
Agou F, Traincard F, Vinolo E, Courtois G, Yamaoka S, Israel A et al. (2004). The trimerization domain of NEMO is composed of the interacting C-terminal CC2 and LZ coiled-coil subdomains. J Biol Chem 279: 27861–27869.
Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M . (1999). Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev 13: 1297–1308.
Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R et al. (2000). Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25: 160–165.
Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C et al. (2004). The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5: 1052–1060.
Brummelkamp TR, Nijman SM, Dirac AM, Bernards R . (2003). Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424: 797–801.
Cannons JL, Bertram EM, Watts TH . (2002). Cutting edge: profound defect in T cell responses in TNF receptor-associated factor 2 dominant negative mice. J Immunol 169: 2828–2831.
Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV . (1996). TRAF6 is a signal transducer for interleukin-1. Nature 383: 443–446.
Chau V, Tobias JW, Bachmair A, Marriott D, Ecker DJ, Gonda DK et al. (1989). A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243: 1576–1583.
Chen ZJ . (2005). Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7: 758–765.
Chen ZJ, Bhoj V, Seth RB . (2006). Ubiquitin, TAK1 and IKK: is there a connection? Cell Death Differ 13: 687–692.
Chen ZJ, Parent L, Maniatis T . (1996). Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 84: 853–862.
Cheung PC, Nebreda AR, Cohen P . (2004). TAB3, a new binding partner of the protein kinase TAK1. Biochem J 378: 27–34.
Chung JY, Park YC, Ye H, Wu H . (2002). All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci 115: 679–688.
Conner SH, Kular G, Peggie M, Shepherd S, Schuttelkopf AW, Cohen P et al. (2006). TAK1-binding protein 1 is a pseudo-phosphatase. Biochem J 399: 427–434.
Cook WJ, Jeffrey LC, Carson M, Chen Z, Pickart CM . (1992). Structure of a diubiquitin conjugate and a model for interaction with ubiquitin conjugating enzyme (E2). J Biol Chem 267: 16467–16471.
Courtois G, Gilmore TD . (2006). Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene 25: 6831–6843.
Delaney JR, Stoven S, Uvell H, Anderson KV, Engstrom Y, Mlodzik M . (2006). Cooperative control of Drosophila immune responses by the JNK and NF-kappaB signaling pathways. EMBO J 25: 3068–3077.
Deng L, Wang C, Spencer E, Yang L, Braun A, You J et al. (2000). Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103: 351–361.
Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ . (2006). Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell 22: 245–257.
Eddins MJ, Carlile CM, Gomez KM, Pickart CM, Wolberger C . (2006). Mms2-Ubc13 covalently bound to ubiquitin reveals the structural basis of linkage-specific polyubiquitin chain formation. Nat Struct Mol Biol 13: 915–920.
Evans PC, Ovaa H, Hamon M, Kilshaw PJ, Hamm S, Bauer S et al. (2004). Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity. Biochem J 378: 727–734.
Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT et al. (2003). IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4: 491–496.
Geuking P, Narasimamurthy R, Basler K . (2005). A genetic screen targeting the tumor necrosis factor/Eiger signaling pathway: identification of Drosophila TAB2 as a functionally conserved component. Genetics 171: 1683–1694.
Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG et al. (2006). Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439: 204–207.
Hauer J, Puschner S, Ramakrishnan P, Simon U, Bongers M, Federle C et al. (2005). TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci USA 102: 2874–2879.
Hicke L, Schubert HL, Hill CP . (2005). Ubiquitin-binding domains. Nat Rev Mol Cell Biol 6: 610–621.
Hofmann RM, Pickart CM . (1999). Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96: 645–653.
Hofmann RM, Pickart CM . (2001). In vitro assembly and recognition of Lys-63 polyubiquitin chains. J Biol Chem 276: 27936–27943.
Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu ZG et al. (2004). Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat Immunol 5: 98–103.
Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S . (2003). Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell 115: 565–576.
Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N et al. (1999). The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 399: 798–802.
Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K . (2003). Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBO J 22: 6277–6288.
Jaeschke A, Karasarides M, Ventura JJ, Ehrhardt A, Zhang C, Flavell RA et al. (2006). JNK2 is a positive regulator of the cJun transcription factor. Mol Cell 23: 899–911.
Janssens S, Tinel A, Lippens S, Tschopp J . (2005). PIDD mediates NF-kappaB activation in response to DNA damage. Cell 123: 1079–1092.
Jiang Z, Ninomiya-Tsuji J, Qian Y, Matsumoto K, Li X . (2002). Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Mol Cell Biol 22: 7158–7167.
Jono H, Lim JH, Chen LF, Xu H, Trompouki E, Pan ZK et al. (2004). NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway. J Biol Chem 279: 36171–36174.
Kajino T, Ren H, Iemura SI, Natsume T, Stefansson B, Brautigan DL et al. (2006). Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway. J Biol Chem 281: 39891–39896.
Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A et al. (2004). TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell 15: 535–548.
Kaneko T, Silverman N . (2005). Bacterial recognition and signalling by the Drosophila IMD pathway. Cell Microbiol 7: 1049–1050.
Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H et al. (2005). IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6: 981–988.
King CG, Kobayashi T, Cejas PJ, Kim T, Yoon K, Kim GK et al. (2006). TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med 12: 1088–1092.
Kleino A, Valanne S, Ulvila J, Kallio J, Myllymaki H, Enwald H et al. (2005). Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Drosophila Imd pathway. EMBO J 24: 3423–3434.
Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S et al. (2001). Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J 20: 1271–1280.
Komatsu Y, Shibuya H, Takeda N, Ninomiya-Tsuji J, Yasui T, Miyado K et al. (2002). Targeted disruption of the Tab1 gene causes embryonic lethality and defects in cardiovascular and lung morphogenesis. Mech Dev 119: 239–249.
Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway CA et al. (1999). ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev 13: 2059–2071.
Kovalenko A, Wallach D . (2006). If the prophet does not come to the mountain: dynamics of signaling complexes in NF-kappaB activation. Mol Cell 22: 433–436.
Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G . (2003). The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424: 801–805.
Krappmann D, Scheidereit C . (2005). A pervasive role of ubiquitin conjugation in activation and termination of IkappaB kinase pathways. EMBO Rep 6: 321–326.
Krikos A, Laherty CD, Dixit VM . (1992). Transcriptional activation of the tumor necrosis factor alpha-inducible zinc-finger protein, A20, is mediated by kappa B elements. J Biol Chem 267: 17971–17976.
Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG . (2007). Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of IkappaB kinase activation. J Biol Chem 282: 4102–4112.
Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP et al. (2000). Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289: 2350–2354.
Lee S, Tsai YC, Mattera R, Smith WJ, Kostelansky MS, Weissman AM et al. (2006). Structural basis for ubiquitin recognition and autoubiquitination by Rabex-5. Nat Struct Mol Biol 13: 264–271.
Lee SY, Reichlin A, Santana A, Sokol KA, Nussenzweig MC, Choi Y . (1997). TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival. Immunity 7: 703–713.
Lee TH, Shank J, Cusson N, Kelliher MA . (2004). The kinase activity of Rip1 is not required for tumor necrosis factor-{alpha}-induced I{kappa}B kinase or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2. J Biol Chem 279: 33185–33191.
Legler DF, Micheau O, Doucey MA, Tschopp J, Bron C . (2003). Recruitment of TNF receptor 1 to lipid rafts is essential for TNFalpha-mediated NF-kappaB activation. Immunity 18: 655–664.
Li H, Kobayashi M, Blonska M, You Y, Lin X . (2006). Ubiquitination of RIP is required for tumor necrosis factor alpha-induced NF-kappaB activation. J Biol Chem 281: 13636–13643.
Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J, Matsumoto K et al. (2003). Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon). J Biol Chem 278: 12013–12021.
Li X, Commane M, Burns C, Vithalani K, Cao Z, Stark GR . (1999). Mutant cells that do not respond to interleukin-1 (IL-1) reveal a novel role for IL-1 receptor-associated kinase. Mol Cell Biol 19: 4643–4652.
Liu HH, Xie M, Schneider MD, Chen ZJ . (2006). Essential role of TAK1 in thymocyte development and activation. Proc Natl Acad Sci USA 103: 11677–11682.
Mabb AM, Wuerzberger-Davis SM, Miyamoto S . (2006). PIASy mediates NEMO sumoylation and NF-kappaB activation in response to genotoxic stress. Nat Cell Biol 8: 986–993.
Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R . (2006). Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 125: 665–677.
Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R et al. (2005). Cardif is an adaptor protein in the RIG-I anti-viral pathway and is targeted by hepatitis C virus. Nature 437: 1167–1172.
Momcilovic M, Hong SP, Carlson M . (2006). Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem 281: 25336–25343.
Muralidhar MG, Thomas JB . (1993). The Drosophila bendless gene encodes a neural protein related to ubiquitin-conjugating enzymes. Neuron 11: 253–266.
Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K . (1999). The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398: 252–256.
Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B et al. (2006). Critical role of TRAF3 in the Toll-like receptor-dependent and -independent anti-viral response. Nature 439: 208–211.
Ono K, Ohtomo T, Sato S, Sugamata Y, Suzuki M, Hisamoto N et al. (2001). An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK. J Biol Chem 276: 24396–24400.
Papa S, Bubici C, Zazzeroni F, Pham CG, Kuntzen C, Knabb JR et al. (2006). The NF-kappaB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease. Cell Death Differ 13: 712–729.
Penengo L, Mapelli M, Murachelli AG, Confalonieri S, Magri L, Musacchio A et al. (2006). Crystal structure of the ubiquitin binding domains of rabex-5 reveals two modes of interaction with ubiquitin. Cell 124: 1183–1195.
Petroski MD, Deshaies RJ . (2005). Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 6: 9–20.
Qin J, Yao J, Cui G, Xiao H, Kim TW, Fraczek J et al. (2006). TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent. J Biol Chem 281: 21013–21021.
Rawlings DJ, Sommer K, Moreno-Garcia ME . (2006). The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat Rev Immunol 6: 799–812.
Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC et al. (2006). Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7: 411–417.
Saha SK, Cheng G . (2006). TRAF3: a new regulator of type I interferons. Cell Cycle 5: 804–807.
Saha SK, Pietras EM, He JQ, Kang JR, Liu SY, Oganesyan G et al. (2006). Regulation of anti-viral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J 25: 3257–3263.
Sanjo H, Takeda K, Tsujimura T, Ninomiya-Tsuji J, Matsumoto K, Akira S . (2003). TAB2 is essential for prevention of apoptosis in fetal liver but not for interleukin-1 signaling. Mol Cell Biol 23: 1231–1238.
Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T et al. (2005). Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat Immunol 6: 1087–1095.
Sato S, Sanjo H, Tsujimura T, Ninomiya-Tsuji J, Yamamoto M, Kawai T et al. (2006). TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells. Int Immunol 18: 1405–1411.
Scheidereit C . (2006). IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene 25: 6685–6705.
Sen R, Baltimore D . (1986a). Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 47: 921–928.
Sen R, Baltimore D . (1986b). Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46: 705–716.
Seth RB, Sun L, Chen ZJ . (2006). Anti-viral innate immunity pathways. Cell Res 16: 141–147.
Seth RB, Sun L, Ea CK, Chen ZJ . (2005). Identification and characterization of MAVS, a mitochondrial anti-viral signaling protein that activates NF-kappaB and IRF 3. Cell 122: 669–682.
Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J . (2003). Triggering the interferon anti-viral response through an IKK-related pathway. Science 300: 1148–1151.
Shi CS, Kehrl JH . (2003). Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2). J Biol Chem 278: 15429–15434.
Shibuya H, Iwata H, Masuyama N, Gotoh Y, Yamaguchi K, Irie K et al. (1998). Role of TAK1 and TAB1 in BMP signaling in early Xenopus development. EMBO J 17: 1019–1028.
Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N et al. (1996). TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science 272: 1179–1182.
Shim JH, Xiao C, Paschal AE, Bailey ST, Rao P, Hayden MS et al. (2005). TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 19: 2668–2681.
Shinohara H, Yasuda T, Aiba Y, Sanjo H, Hamadate M, Watarai H et al. (2005). PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J Exp Med 202: 1423–1431.
Silverman N, Zhou R, Erlich RL, Hunter M, Bernstein E, Schneider D et al. (2003). Immune activation of NF-kappaB and JNK requires Drosophila TAK1. J Biol Chem 278: 48928–48934.
Smit L, Baas A, Kuipers J, Korswagen H, van de Wetering M, Clevers H . (2004). Wnt activates the Tak1/Nemo-like kinase pathway. J Biol Chem 279: 17232–17240.
Spence J, Sadis S, Haas AL, Finley D . (1995). A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol Cell Biol 15: 1265–1273.
Sun L, Chen ZJ . (2004). The novel functions of ubiquitination in signaling. Curr Opin Cell Biol 16: 119–126.
Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ . (2004). The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell 14: 289–301.
Tada K, Okazaki T, Sakon S, Kobarai T, Kurosawa K, Yamaoka S et al. (2001). Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death. J Biol Chem 276: 36530–36534.
Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K et al. (2000). TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell 5: 649–658.
Takeuchi M, Rothe M, Goeddel DV . (1996). Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins. J Biol Chem 271: 19935–19942.
Tang ED, Wang CY, Xiong Y, Guan KL . (2003). A role for NF-kappaB essential modifier/IkappaB kinase-gamma (NEMO/IKKgamma) ubiquitination in the activation of the IkappaB kinase complex by tumor necrosis factor-alpha. J Biol Chem 278: 37297–37305.
Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G . (2003). CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424: 793–796.
VanDemark AP, Hofmann RM, Tsui C, Pickart CM, Wolberger C . (2001). Molecular insights into polyubiquitin chain assembly: crystal structure of the Mms2/Ubc13 heterodimer. Cell 105: 711–720.
Varadan R, Assfalg M, Haririnia A, Raasi S, Pickart C, Fushman D . (2004). Solution conformation of Lys63-linked diubiquitin chain provides clues to functional diversity of polyubiquitin signaling. J Biol Chem 279: 7055–7063.
Vidal S, Khush RS, Leulier F, Tzou P, Nakamura M, Lemaitre B . (2001). Mutations in the Drosophila dTAK1 gene reveal a conserved function for MAPKKKs in the control of rel/NF-kappaB-dependent innate immune responses. Genes Dev 15: 1900–1912.
Wan YY, Chi H, Xie M, Schneider MD, Flavell RA . (2006). The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat Immunol 7: 851–858.
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ . (2001). TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412: 346–351.
Weil R, Israel A . (2006). Deciphering the pathway from the TCR to NF-kappaB. Cell Death Differ 13: 826–833.
Wertz IE, O’Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S et al. (2004). De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430: 694–699.
Wu CJ, Conze DB, Li T, Srinivasula SM, Ashwell JD . (2006a). NEMO is a sensor of Lys 63-linked polyubiquitination and functions in NF-kappaB activation. Nat Cell Biol 8: 398–406.
Wu H, Arron JR . (2003). TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays 25: 1096–1105.
Wu ZH, Shi Y, Tibbetts RS, Miyamoto S . (2006b). Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science 311: 1141–1146.
Xiao C, Shim JH, Kluppel M, Zhang SS, Dong C, Flavell RA et al. (2003). Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis. Genes Dev 17: 2933–2949.
Xie M, Zhang D, Dyck JR, Li Y, Zhang H, Morishima M et al. (2006). A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc Natl Acad Sci USA 103: 17378–17383.
Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB . (2005). VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19: 727–740.
Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N et al. (1995). Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270: 2008–2011.
Yamamoto M, Okamoto T, Takeda K, Sato S, Sanjo H, Uematsu S et al. (2006a). Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol 7: 962–970.
Yamamoto M, Sato S, Saitoh T, Sakurai H, Uematsu S, Kawai T et al. (2006b). Cutting edge: pivotal function of Ubc13 in thymocyte TCR signaling. J Immunol 177: 7520–7524.
Yang J, Lin Y, Guo Z, Cheng J, Huang J, Deng L et al. (2001). The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nat Immunol 2: 620–624.
Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A et al. (1997). Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7: 715–725.
Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M et al. (2004). The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate anti-viral responses. Nat Immunol 5: 730–737.
Yujiri T, Ware M, Widmann C, Oyer R, Russell D, Chan E et al. (2000). MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation. Proc Natl Acad Sci USA 97: 7272–7277.
Zhang J, Stirling B, Temmerman ST, Ma CA, Fuss IJ, Derry JM et al. (2006). Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. J Clin Invest 116: 3042–3049.
Zhang SQ, Kovalenko A, Cantarella G, Wallach D . (2000). Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity 12: 301–311.
Zhou H, Wertz I, O’Rourke K, Ultsch M, Seshagiri S, Eby M et al. (2004). Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 427: 167–171.
Zhou R, Silverman N, Hong M, Liao DS, Chung Y, Chen ZJ et al. (2005). The role of ubiquitination in Drosophila innate immunity. J Biol Chem 280: 34048–34055.
Zhuang ZH, Sun L, Kong L, Hu JH, Yu MC, Reinach P et al. (2006). Drosophila TAB2 is required for the immune activation of JNK and NF-kappaB. Cell Signal 18: 964–970.
Acknowledgements
Research in the Chen laboratory is supported by grants from NIH and the Welch Foundation. ZJC is a Burroughs Wellcome Investigator in Pathogenesis of Infectious Diseases and an Investigator of the Howard Hughes Medical Institute.
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Adhikari, A., Xu, M. & Chen, Z. Ubiquitin-mediated activation of TAK1 and IKK. Oncogene 26, 3214–3226 (2007). https://doi.org/10.1038/sj.onc.1210413
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PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
Nature Communications (2019)