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PDBsum entry 1lb6

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protein ligands links
Signaling protein PDB id
1lb6
Jmol
Contents
Protein chain
155 a.a. *
Ligands
LYS-GLN-GLU-PRO-
GLN-GLU-ILE-ASP-
PHE
Waters ×122
* Residue conservation analysis
PDB id:
1lb6
Name: Signaling protein
Title: Traf6-cd40 complex
Structure: Tnf receptor-associated factor 6. Chain: a. Fragment: residues 347-504. Engineered: yes. Cd40 antigen. Chain: b. Fragment: residues 230-238. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: traf6. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: cd40. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
1.80Å     R-factor:   0.203     R-free:   0.258
Authors: H.Ye,J.R.Arron,B.Lamothe,M.Cirilli,T.Kobayashi,N.K.Shevde, D.Segal,O.Dzivenu,M.Vologodskaia,M.Yim,K.Du,S.Singh, J.W.Pike,B.G.Darnay,Y.Choi,H.Wu
Key ref:
H.Ye et al. (2002). Distinct molecular mechanism for initiating TRAF6 signalling. Nature, 418, 443-447. PubMed id: 12140561 DOI: 10.1038/nature00888
Date:
02-Apr-02     Release date:   31-Jul-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9Y4K3  (TRAF6_HUMAN) -  TNF receptor-associated factor 6
Seq:
Struc:
 
Seq:
Struc:
522 a.a.
155 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     bone remodeling   13 terms 
  Biochemical function     signal transducer activity     2 terms  

 

 
DOI no: 10.1038/nature00888 Nature 418:443-447 (2002)
PubMed id: 12140561  
 
 
Distinct molecular mechanism for initiating TRAF6 signalling.
H.Ye, J.R.Arron, B.Lamothe, M.Cirilli, T.Kobayashi, N.K.Shevde, D.Segal, O.K.Dzivenu, M.Vologodskaia, M.Yim, K.Du, S.Singh, J.W.Pike, B.G.Darnay, Y.Choi, H.Wu.
 
  ABSTRACT  
 
Tumour-necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is the only TRAF family member that participates in signal transduction of both the TNF receptor (TNFR) superfamily and the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily; it is important for adaptive immunity, innate immunity and bone homeostasis. Here we report crystal structures of TRAF6, alone and in complex with TRAF6-binding peptides from CD40 and TRANCE-R (also known as RANK), members of the TNFR superfamily, to gain insight into the mechanism by which TRAF6 mediates several signalling cascades. A 40 degrees difference in the directions of the bound peptides in TRAF6 and TRAF2 shows that there are marked structural differences between receptor recognition by TRAF6 and other TRAFs. The structural determinant of the petide TRAF6 interaction reveals a Pro-X-Glu-X-X-(aromatic/acidic residue) TRAF6-binding motif, which is present not only in CD40 and TRANCE-R but also in the three IRAK adapter kinases for IL-1R/TLR signalling. Cell-permeable peptides with the TRAF6-binding motif inhibit TRAF6 signalling, which indicates their potential as therapeutic modulators. Our studies identify a universal mechanism by which TRAF6 regulates several signalling cascades in adaptive immunity, innate immunity and bone homeostasis.
 
  Selected figure(s)  
 
Figure 1.
Figure 1: TRAF6 structures. a, Ribbon diagram of the TRAF domain of TRAF6 in complex with TRANCE-R, shown as a trimeric model by applying the putative three-fold symmetry observed in TRAF2 structures6. b, Worm C traces of superimposed TRAF6 and TRAF2 structures. c, Surface representation of TRAF6, coloured on the basis of electrostatic potential (-10k[b]T/e to +10k[b]T/e, where k[b], T and e are the Boltzmann constant, temperature and the electron charge, respectively), and the bound TRANCE-R peptide. d, Surface representation of TRAF2, shown with the bound core CD40 peptide. e, Interaction between TRAF6 and the TRANCE-R peptide. Main-chain hydrogen bonds between the TRANCE-R peptide and the 7 strand of TRAF6 are shown as dotted lines. Side chains of some of the 7 residues are omitted for clarity. f, Superposition of the TRANCE-R and the CD40 peptide. g, The Pro-X-Glu-X-X-(Ar/Ac) TRAF6-binding motif. The surface area buried (SAB) on TRAF6 interaction for the eight contacting residues (P[-4] to P[3]) is shown. CD40 residues that were mutated to assess their effect on in vitro interaction with TRAF6 are indicated on top by a circle (open, does not abolish interaction; filled, abolishes interaction). h, Presence of one or many Pro-X-Glu-X-X-(Ar/Ac) motifs in TRANCE-R, IRAK, IRAK-2, IRAK-M and RIP2.
Figure 2.
Figure 2: Functional analyses for the interaction of TRAF6 with CD40, TRANCE-R and IRAK. a, NF- B induction by mouse CD40. b, NF- B induction by mouse TRANCE-R (mTR). c, NF- B induction by human IRAK. d, Inhibition of endogenous IL-1 signalling by mouse T6.DN (residues are numbered on the basis of human TRAF6).
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2002, 418, 443-447) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21135870 C.Zheng, Q.Yin, and H.Wu (2011).
Structural studies of NF-κB signaling.
  Cell Res, 21, 183-195.  
21155952 H.Motegi, Y.Shimo, T.Akiyama, and J.Inoue (2011).
TRAF6 negatively regulates the Jak1-Erk pathway in interleukin-2 signaling.
  Genes Cells, 16, 179-189.  
20816892 P.H.Wang, D.H.Wan, Z.H.Gu, X.X.Deng, S.P.Weng, X.Q.Yu, and J.G.He (2011).
Litopenaeus vannamei tumor necrosis factor receptor-associated factor 6 (TRAF6) responds to Vibrio alginolyticus and white spot syndrome virus (WSSV) infection and activates antimicrobial peptide genes.
  Dev Comp Immunol, 35, 105-114.  
19649704 C.Gangadharan, M.Thoh, and S.K.Manna (2010).
Late phase activation of nuclear transcription factor kappaB by doxorubicin is mediated by interleukin-8 and induction of apoptosis via FasL.
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20953188 E.Ellinghaus, D.Ellinghaus, P.E.Stuart, R.P.Nair, S.Debrus, J.V.Raelson, M.Belouchi, H.Fournier, C.Reinhard, J.Ding, Y.Li, T.Tejasvi, J.Gudjonsson, S.W.Stoll, J.J.Voorhees, S.Lambert, S.Weidinger, B.Eberlein, M.Kunz, P.Rahman, D.D.Gladman, C.Gieger, H.E.Wichmann, T.H.Karlsen, G.Mayr, M.Albrecht, D.Kabelitz, U.Mrowietz, G.R.Abecasis, J.T.Elder, S.Schreiber, M.Weichenthal, and A.Franke (2010).
Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
  Nat Genet, 42, 991-995.  
20067410 J.Chen, H.C.He, Q.J.Xia, L.Q.Huang, Y.J.Hu, and C.Q.He (2010).
Effects of pulsed electromagnetic fields on the mRNA expression of RANK and CAII in ovariectomized rat osteoclast-like cell.
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  20230632 J.M.González, and M.Esteban (2010).
A poxvirus Bcl-2-like gene family involved in regulation of host immune response: sequence similarity and evolutionary history.
  Virol J, 7, 59.  
20512936 K.Z.Wang, D.L.Galson, and P.E.Auron (2010).
TRAF6 is autoinhibited by an intramolecular interaction which is counteracted by trans-ubiquitination.
  J Cell Biochem, 110, 763-771.  
20384865 L.Li, X.P.Chen, and Y.J.Li (2010).
MicroRNA-146a and human disease.
  Scand J Immunol, 71, 227-231.  
20932475 M.Hinz, M.Stilmann, S...Arslan, K.K.Khanna, G.Dittmar, and C.Scheidereit (2010).
A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation.
  Mol Cell, 40, 63-74.  
20644648 P.Stachon, A.Missiou, C.Walter, N.Varo, C.Colberg, D.Wolf, M.Buchner, C.von Zur Mühlen, K.Zirlik, C.Bode, and A.Zirlik (2010).
Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans.
  PLoS One, 5, e11589.  
20497537 S.K.Yang, Y.C.Wang, C.C.Chao, Y.J.Chuang, C.Y.Lan, and B.S.Chen (2010).
Dynamic cross-talk analysis among TNF-R, TLR-4 and IL-1R signalings in TNFalpha-induced inflammatory responses.
  BMC Med Genomics, 3, 19.  
  20081374 W.L.Yang, C.Y.Wu, J.Wu, and H.K.Lin (2010).
Regulation of Akt signaling activation by ubiquitination.
  Cell Cycle, 9, 487-497.  
19592497 B.Verstak, K.Nagpal, S.P.Bottomley, D.T.Golenbock, P.J.Hertzog, and A.Mansell (2009).
MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses.
  J Biol Chem, 284, 24192-24203.  
19012753 J.C.Powell, C.Twomey, R.Jain, and J.V.McCarthy (2009).
Association between Presenilin-1 and TRAF6 modulates regulated intramembrane proteolysis of the p75NTR neurotrophin receptor.
  J Neurochem, 108, 216-230.  
19184540 K.A.Mensah, J.Li, and E.M.Schwarz (2009).
The emerging field of osteoimmunology.
  Immunol Res, 45, 100-113.  
19818708 M.Zhuang, M.F.Calabrese, J.Liu, M.B.Waddell, A.Nourse, M.Hammel, D.J.Miller, H.Walden, D.M.Duda, S.N.Seyedin, T.Hoggard, J.W.Harper, K.P.White, and B.A.Schulman (2009).
Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases.
  Mol Cell, 36, 39-50.
PDB codes: 3hqh 3hqi 3hql 3hqm 3hsv 3htm 3hu6 3hve 3ivq 3ivv
19376060 P.A.Barker (2009).
A p75(NTR) pivoting paradigm propels perspicacity.
  Neuron, 62, 3-5.  
19810754 Q.Yin, B.Lamothe, B.G.Darnay, and H.Wu (2009).
Structural basis for the lack of E2 interaction in the RING domain of TRAF2.
  Biochemistry, 48, 10558-10567.
PDB code: 3knv
19465916 Q.Yin, S.C.Lin, B.Lamothe, M.Lu, Y.C.Lo, G.Hura, L.Zheng, R.L.Rich, A.D.Campos, D.G.Myszka, M.J.Lenardo, B.G.Darnay, and H.Wu (2009).
E2 interaction and dimerization in the crystal structure of TRAF6.
  Nat Struct Mol Biol, 16, 658-666.
PDB codes: 3hcs 3hct 3hcu
19270748 T.Kobayashi, T.S.Kim, A.Jacob, M.C.Walsh, Y.Kadono, E.Fuentes-Pananá, T.Yoshioka, A.Yoshimura, M.Yamamoto, T.Kaisho, S.Akira, J.G.Monroe, and Y.Choi (2009).
TRAF6 is required for generation of the B-1a B cell compartment as well as T cell-dependent and -independent humoral immune responses.
  PLoS ONE, 4, e4736.  
18617513 B.Lamothe, A.D.Campos, W.K.Webster, A.Gopinathan, L.Hur, and B.G.Darnay (2008).
The RING Domain and First Zinc Finger of TRAF6 Coordinate Signaling by Interleukin-1, Lipopolysaccharide, and RANKL.
  J Biol Chem, 283, 24871-24880.  
18347055 D.B.Conze, C.J.Wu, J.A.Thomas, A.Landstrom, and J.D.Ashwell (2008).
Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation.
  Mol Cell Biol, 28, 3538-3547.  
18983698 I.E.Adamopoulos, and E.P.Bowman (2008).
Immune regulation of bone loss by Th17 cells.
  Arthritis Res Ther, 10, 225.  
18411265 J.Hartupee, X.Li, and T.Hamilton (2008).
Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1.
  J Biol Chem, 283, 15689-15693.  
18668204 J.S.Orange, and M.J.May (2008).
Cell penetrating peptide inhibitors of nuclear factor-kappa B.
  Cell Mol Life Sci, 65, 3564-3591.  
19112497 M.C.Walsh, G.K.Kim, P.L.Maurizio, E.E.Molnar, and Y.Choi (2008).
TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL.
  PLoS ONE, 3, e4064.  
18679808 M.G.Lerner, K.L.Meagher, and H.A.Carlson (2008).
Automated clustering of probe molecules from solvent mapping of protein surfaces: new algorithms applied to hot-spot mapping and structure-based drug design.
  J Comput Aided Mol Des, 22, 727-736.  
18824541 M.Y.Balkhi, K.A.Fitzgerald, and P.M.Pitha (2008).
Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitination.
  Mol Cell Biol, 28, 7296-7308.  
18984593 R.Yoshida, G.Takaesu, H.Yoshida, F.Okamoto, T.Yoshioka, Y.Choi, S.Akira, T.Kawai, A.Yoshimura, and T.Kobayashi (2008).
TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway.
  J Biol Chem, 283, 36211-36220.  
18682563 X.Liu, K.Fitzgerald, E.Kurt-Jones, R.Finberg, and D.M.Knipe (2008).
Herpesvirus tegument protein activates NF-kappaB signaling through the TRAF6 adaptor protein.
  Proc Natl Acad Sci U S A, 105, 11335-11339.  
18772140 Y.J.Yang, W.Chen, S.O.Carrigan, W.M.Chen, K.Roth, T.Akiyama, J.Inoue, J.S.Marshall, J.N.Berman, and T.J.Lin (2008).
TRAF6 Specifically Contributes to Fc{epsilon}RI-mediated Cytokine Production but Not Mast Cell Degranulation.
  J Biol Chem, 283, 32110-32118.  
18302500 Z.Zhou, J.Y.Han, C.X.Xi, J.X.Xie, X.Feng, C.Y.Wang, L.Mei, and W.C.Xiong (2008).
HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE.
  J Bone Miner Res, 23, 1084-1096.  
17158449 A.Besse, B.Lamothe, A.D.Campos, W.K.Webster, U.Maddineni, S.C.Lin, H.Wu, and B.G.Darnay (2007).
TAK1-dependent signaling requires functional interaction with TAB2/TAB3.
  J Biol Chem, 282, 3918-3928.  
17135271 B.Lamothe, A.Besse, A.D.Campos, W.K.Webster, H.Wu, and B.G.Darnay (2007).
Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
  J Biol Chem, 282, 4102-4112.  
17572386 B.Lamothe, W.K.Webster, A.Gopinathan, A.Besse, A.D.Campos, and B.G.Darnay (2007).
TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation.
  Biochem Biophys Res Commun, 359, 1044-1049.  
17917059 B.S.Hostager (2007).
Roles of TRAF6 in CD40 signaling.
  Immunol Res, 39, 105-114.  
17329168 E.A.Wohlfert, and R.B.Clark (2007).
'Vive la Résistance!'--the PI3K-Akt pathway can determine target sensitivity to regulatory T cell suppression.
  Trends Immunol, 28, 154-160.  
17197697 J.Yao, T.W.Kim, J.Qin, Z.Jiang, Y.Qian, H.Xiao, Y.Lu, W.Qian, M.F.Gulen, N.Sizemore, J.DiDonato, S.Sato, S.Akira, B.Su, and X.Li (2007).
Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification.
  J Biol Chem, 282, 6075-6089.  
17288531 M.Baud'huin, L.Duplomb, C.Ruiz Velasco, Y.Fortun, D.Heymann, and M.Padrines (2007).
Key roles of the OPG-RANK-RANKL system in bone oncology.
  Expert Rev Anticancer Ther, 7, 221-232.  
17182673 M.I.Garcia, J.Kaserman, Y.H.Chung, J.U.Jung, and S.H.Lee (2007).
Herpesvirus saimiri STP-A oncoprotein utilizes Src family protein tyrosine kinase and tumor necrosis factor receptor-associated factors to elicit cellular signal transduction.
  J Virol, 81, 2663-2674.  
17560374 M.Lu, S.C.Lin, Y.Huang, Y.J.Kang, R.Rich, Y.C.Lo, D.Myszka, J.Han, and H.Wu (2007).
XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization.
  Mol Cell, 26, 689-702.
PDB codes: 2poi 2pom 2pop
17341304 P.E.Poubelle, A.Chakravarti, M.J.Fernandes, K.Doiron, and A.A.Marceau (2007).
Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human blood neutrophils.
  Arthritis Res Ther, 9, R25.  
17327397 P.Mercier, M.J.Lewis, D.D.Hau, L.F.Saltibus, W.Xiao, and L.Spyracopoulos (2007).
Structure, interactions, and dynamics of the RING domain from human TRAF6.
  Protein Sci, 16, 602-614.
PDB code: 2jmd
17878161 S.E.Keating, G.M.Maloney, E.M.Moran, and A.G.Bowie (2007).
IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination.
  J Biol Chem, 282, 33435-33443.  
  17255310 S.L.Teitelbaum (2007).
Osteoclasts: what do they do and how do they do it?
  Am J Pathol, 170, 427-435.  
17092936 Y.Feng, H.Zhao, H.F.Luderer, H.Epple, R.Faccio, F.P.Ross, S.L.Teitelbaum, and G.D.Longmore (2007).
The LIM protein, Limd1, regulates AP-1 activation through an interaction with Traf6 to influence osteoclast development.
  J Biol Chem, 282, 39-48.  
16921377 C.G.King, T.Kobayashi, P.J.Cejas, T.Kim, K.Yoon, G.K.Kim, E.Chiffoleau, S.P.Hickman, P.T.Walsh, L.A.Turka, and Y.Choi (2006).
TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis.
  Nat Med, 12, 1088-1092.  
16894359 D.Jiang, J.Liang, Y.Li, and P.W.Noble (2006).
The role of Toll-like receptors in non-infectious lung injury.
  Cell Res, 16, 693-701.  
16373338 D.Xu, S.Wang, W.Liu, J.Liu, and X.Feng (2006).
A novel receptor activator of NF-kappaB (RANK) cytoplasmic motif plays an essential role in osteoclastogenesis by committing macrophages to the osteoclast lineage.
  J Biol Chem, 281, 4678-4690.  
16702955 H.Chen, M.Li, R.A.Campbell, K.Burkhardt, D.Zhu, S.G.Li, H.J.Lee, C.Wang, Z.Zeng, M.S.Gordon, B.Bonavida, and J.R.Berenson (2006).
Interference with nuclear factor kappa B and c-Jun NH2-terminal kinase signaling by TRAF6C small interfering RNA inhibits myeloma cell proliferation and enhances apoptosis.
  Oncogene, 25, 6520-6527.  
16825662 J.H.Thomas (2006).
Adaptive evolution in two large families of ubiquitin-ligase adapters in nematodes and plants.
  Genome Res, 16, 1017-1030.  
17072332 J.Hiscott, T.L.Nguyen, M.Arguello, P.Nakhaei, and S.Paz (2006).
Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses.
  Oncogene, 25, 6844-6867.  
16382137 J.Wan, W.Zhang, L.Wu, T.Bai, M.Zhang, K.W.Lo, Y.L.Chui, Y.Cui, Q.Tao, M.Yamamoto, S.Akira, and Z.Wu (2006).
BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway.
  Mol Cell Biol, 26, 448-456.  
16436380 L.He, X.Wu, R.Siegel, and P.E.Lipsky (2006).
TRAF6 regulates cell fate decisions by inducing caspase 8-dependent apoptosis and the activation of NF-kappaB.
  J Biol Chem, 281, 11235-11249.  
17183684 M.Baens, H.Noels, V.Broeckx, S.Hagens, S.Fevery, A.D.Billiau, H.Vankelecom, and P.Marynen (2006).
The dark side of EGFP: defective polyubiquitination.
  PLoS ONE, 1, e54.  
16551243 M.C.Walsh, N.Kim, Y.Kadono, J.Rho, S.Y.Lee, J.Lorenzo, and Y.Choi (2006).
Osteoimmunology: interplay between the immune system and bone metabolism.
  Annu Rev Immunol, 24, 33-63.  
16402859 M.Hu, L.Gu, M.Li, P.D.Jeffrey, W.Gu, and Y.Shi (2006).
Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.
  PLoS Biol, 4, e27.
PDB codes: 2f1w 2f1x 2f1y 2f1z
16920630 N.Bidère, A.L.Snow, K.Sakai, L.Zheng, and M.J.Lenardo (2006).
Caspase-8 regulation by direct interaction with TRAF6 in T cell receptor-induced NF-kappaB activation.
  Curr Biol, 16, 1666-1671.  
16328957 N.K.Lee, H.K.Choi, D.K.Kim, and S.Y.Lee (2006).
Rac1 GTPase regulates osteoclast differentiation through TRANCE-induced NF-kappaB activation.
  Mol Cell Biochem, 281, 55-61.  
16574867 N.Suzuki, S.Suzuki, D.G.Millar, M.Unno, H.Hara, T.Calzascia, S.Yamasaki, T.Yokosuka, N.J.Chen, A.R.Elford, J.Suzuki, A.Takeuchi, C.Mirtsos, D.Bouchard, P.S.Ohashi, W.C.Yeh, and T.Saito (2006).
A critical role for the innate immune signaling molecule IRAK-4 in T cell activation.
  Science, 311, 1927-1932.  
17046325 N.Suzuki, and T.Saito (2006).
IRAK-4--a shared NF-kappaB activator in innate and acquired immunity.
  Trends Immunol, 27, 566-572.  
16452479 S.Heinemann, B.Biesinger, B.Fleckenstein, and J.C.Albrecht (2006).
NFkappaB signaling is induced by the oncoprotein Tio through direct interaction with TRAF6.
  J Biol Chem, 281, 8565-8572.  
16945019 T.Chen, and X.Feng (2006).
Cell-based assay strategy for identification of motif-specific RANK signaling pathway inhibitors.
  Assay Drug Dev Technol, 4, 473-482.  
16831874 W.Dong, Y.Liu, J.Peng, L.Chen, T.Zou, H.Xiao, Z.Liu, W.Li, Y.Bu, and Y.Qi (2006).
The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4.
  J Biol Chem, 281, 26029-26040.  
16619004 Y.H.Paik, K.S.Lee, H.J.Lee, K.M.Yang, S.J.Lee, D.K.Lee, K.H.Han, C.Y.Chon, S.I.Lee, Y.M.Moon, and D.A.Brenner (2006).
Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid.
  Lab Invest, 86, 676-686.  
16474402 Y.Sheng, V.Saridakis, F.Sarkari, S.Duan, T.Wu, C.H.Arrowsmith, and L.Frappier (2006).
Molecular recognition of p53 and MDM2 by USP7/HAUSP.
  Nat Struct Mol Biol, 13, 285-291.
PDB codes: 2foj 2foo 2fop
16378096 Y.Wang, Y.Tang, L.Teng, Y.Wu, X.Zhao, and G.Pei (2006).
Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling.
  Nat Immunol, 7, 139-147.  
16260598 C.C.Davies, T.W.Mak, L.S.Young, and A.G.Eliopoulos (2005).
TRAF6 is required for TRAF2-dependent CD40 signal transduction in nonhemopoietic cells.
  Mol Cell Biol, 25, 9806-9819.  
16313342 E.Jimi, and S.Ghosh (2005).
Role of nuclear factor-kappaB in the immune system and bone.
  Immunol Rev, 208, 80-87.  
16052631 F.Takeshita, K.J.Ishii, K.Kobiyama, Y.Kojima, C.Coban, S.Sasaki, N.Ishii, D.M.Klinman, K.Okuda, S.Akira, and K.Suzuki (2005).
TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF.
  Eur J Immunol, 35, 2477-2485.  
15765185 H.Takatsuna, M.Asagiri, T.Kubota, K.Oka, T.Osada, C.Sugiyama, H.Saito, K.Aoki, K.Ohya, H.Takayanagi, and K.Umezawa (2005).
Inhibition of RANKL-induced osteoclastogenesis by (-)-DHMEQ, a novel NF-kappaB inhibitor, through downregulation of NFATc1.
  J Bone Miner Res, 20, 653-662.  
15678102 J.Gohda, T.Akiyama, T.Koga, H.Takayanagi, S.Tanaka, and J.Inoue (2005).
RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis.
  EMBO J, 24, 790-799.  
16234979 K.Kanazawa, and A.Kudo (2005).
Self-assembled RANK induces osteoclastogenesis ligand-independently.
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16153868 L.G.Xu, Y.Y.Wang, K.J.Han, L.Y.Li, Z.Zhai, and H.B.Shu (2005).
VISA is an adapter protein required for virus-triggered IFN-beta signaling.
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16079148 M.W.Wooten, T.Geetha, M.L.Seibenhener, J.R.Babu, M.T.Diaz-Meco, and J.Moscat (2005).
The p62 scaffold regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination.
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16125763 R.B.Seth, L.Sun, C.K.Ea, and Z.J.Chen (2005).
Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3.
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16221674 R.Mashima, K.Saeki, D.Aki, Y.Minoda, H.Takaki, T.Sanada, T.Kobayashi, H.Aburatani, Y.Yamanashi, and A.Yoshimura (2005).
FLN29, a novel interferon- and LPS-inducible gene acting as a negative regulator of toll-like receptor signaling.
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16184196 S.Bai, H.Kitaura, H.Zhao, J.Chen, J.M.Müller, R.Schüle, B.Darnay, D.V.Novack, F.P.Ross, and S.L.Teitelbaum (2005).
FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner.
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15591054 S.K.Manna, and G.T.Ramesh (2005).
Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway.
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16219697 S.Matsuzawa, M.Cuddy, T.Fukushima, and J.C.Reed (2005).
Method for targeting protein destruction by using a ubiquitin-independent, proteasome-mediated degradation pathway.
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16313339 S.Tanaka, K.Nakamura, N.Takahasi, and T.Suda (2005).
Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system.
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16009714 S.Wu, P.Xie, K.Welsh, C.Li, C.Z.Ni, X.Zhu, J.C.Reed, A.C.Satterthwait, G.A.Bishop, and K.R.Ely (2005).
LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B lymphocytes for binding to TRAF3.
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PDB code: 1zms
16246731 T.Geetha, J.Jiang, and M.W.Wooten (2005).
Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling.
  Mol Cell, 20, 301-312.  
16252010 T.Geetha, R.S.Kenchappa, M.W.Wooten, and B.D.Carter (2005).
TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor.
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15808506 V.Saridakis, Y.Sheng, F.Sarkari, M.N.Holowaty, K.Shire, T.Nguyen, R.G.Zhang, J.Liao, W.Lee, A.M.Edwards, C.H.Arrowsmith, and L.Frappier (2005).
Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.
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PDB codes: 1yy6 1yze
16260781 W.Liu, S.Wang, S.Wei, L.Sun, and X.Feng (2005).
Receptor activator of NF-kappaB (RANK) cytoplasmic motif, 369PFQEP373, plays a predominant role in osteoclast survival in part by activating Akt/PKB and its downstream effector AFX/FOXO4.
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15777737 X.Feng (2005).
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Strength of TRAF6 signalling determines osteoclastogenesis.
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14645259 A.C.Bharti, Y.Takada, S.Shishodia, and B.B.Aggarwal (2004).
Evidence that receptor activator of nuclear factor (NF)-kappaB ligand can suppress cell proliferation and induce apoptosis through activation of a NF-kappaB-independent and TRAF6-dependent mechanism.
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15247281 A.Mansell, E.Brint, J.A.Gould, L.A.O'Neill, and P.J.Hertzog (2004).
Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kappaB activation by toll-like receptor (TLR)-2 and TLR4.
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15108355 A.Wattel, S.Kamel, C.Prouillet, J.P.Petit, F.Lorget, E.Offord, and M.Brazier (2004).
Flavonoid quercetin decreases osteoclastic differentiation induced by RANKL via a mechanism involving NF kappa B and AP-1.
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TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6.
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14625308 C.Kollewe, A.C.Mackensen, D.Neumann, J.Knop, P.Cao, S.Li, H.Wesche, and M.U.Martin (2004).
Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling.
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14960584 J.J.Gentry, N.J.Rutkoski, T.L.Burke, and B.D.Carter (2004).
A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF.
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14673155 J.Wan, L.Sun, J.W.Mendoza, Y.L.Chui, D.P.Huang, Z.J.Chen, N.Suzuki, S.Suzuki, W.C.Yeh, S.Akira, K.Matsumoto, Z.G.Liu, and Z.Wu (2004).
Elucidation of the c-Jun N-terminal kinase pathway mediated by Estein-Barr virus-encoded latent membrane protein 1.
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15247511 K.Matsuo, and N.Ray (2004).
Osteoclasts, mononuclear phagocytes, and c-Fos: new insight into osteoimmunology.
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15340068 M.L.Seibenhener, J.R.Babu, T.Geetha, H.C.Wong, N.R.Krishna, and M.W.Wooten (2004).
Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation.
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14699109 R.A.Veach, D.Liu, S.Yao, Y.Chen, X.Y.Liu, S.Downs, and J.Hawiger (2004).
Receptor/transporter-independent targeting of functional peptides across the plasma membrane.
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15229469 S.Akira, and K.Takeda (2004).
Toll-like receptor signalling.
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15069060 S.H.Rhee, A.C.Keates, M.P.Moyer, and C.Pothoulakis (2004).
MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells.
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Use of cell-permeable peptides to prevent neuronal degeneration.
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15485878 W.Liu, D.Xu, H.Yang, H.Xu, Z.Shi, X.Cao, S.Takeshita, J.Liu, M.Teale, and X.Feng (2004).
Functional identification of three receptor activator of NF-kappa B cytoplasmic motifs mediating osteoclast differentiation and function.
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15314148 W.Wu, R.D.Mosteller, and D.Broek (2004).
Sphingosine kinase protects lipopolysaccharide-activated macrophages from apoptosis.
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Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta.
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Dexamethasone enhances osteoclast formation synergistically with transforming growth factor-beta by stimulating the priming of osteoclast progenitors for differentiation into osteoclasts.
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14517219 C.Li, P.S.Norris, C.Z.Ni, M.L.Havert, E.M.Chiong, B.R.Tran, E.Cabezas, J.C.Reed, A.C.Satterthwait, C.F.Ware, and K.R.Ely (2003).
Structurally distinct recognition motifs in lymphotoxin-beta receptor and CD40 for tumor necrosis factor receptor-associated factor (TRAF)-mediated signaling.
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PDB code: 1rf3
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Distinctions between c-Rel and other NF-kappaB proteins in immunity and disease.
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TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology.
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HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk.
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TNF-receptor-associated factors as targets for drug development.
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TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling.
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Biology of the TRANCE axis.
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Toll-like receptor signaling.
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12620219 S.Janssens, and R.Beyaert (2003).
Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members.
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12556207 S.L.Kalled, C.Ambrose, and Y.M.Hsu (2003).
BAFF: B cell survival factor and emerging therapeutic target for autoimmune disorders.
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Genetic regulation of osteoclast development and function.
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TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor.
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hSef inhibits PC-12 cell differentiation by interfering with Ras-mitogen-activated protein kinase MAPK signaling.
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Osteoclast differentiation and activation.
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Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex.
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Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR .
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Role of TRAF3 and -6 in the activation of the NF-kappa B and JNK pathways by X-linked ectodermal dysplasia receptor.
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The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.