TRAF6 (TNF receptor associated factor 6)

Gene

• Entrez ID: 7189
• Gene name: TNF receptor associated factor 6
• Gene symbol: TRAF6
• Synonyms: MGC:3310, RNF85
• Chromosome: 11
• Chromosome location: 11p12
• Summary: The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from, members of the TNF receptor superfamily. This protein mediates signaling from members of the TNF receptor superfamily as well as the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/RANCE and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. This protein also interacts with the transforming growth factor (TGF) beta receptor complex and is required for Smad-independent activation of the JNK and p38 kinases. This protein has an amino terminal RING domain which is followed by four zinc-finger motifs, a central coiled-coil region and a highly conserved carboxyl terminal domain, known as the TRAF-C domain. Two alternatively spliced transcript variants, encoding an identical protein, have been reported. [provided by RefSeq, Feb 2012]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT000711	hsa-miR-146a-5p	Western blot, Northern blot	18504431
MIRT000711	hsa-miR-146a-5p	Luciferase reporter assay, Western blot	20061417
MIRT000711	hsa-miR-146a-5p	qRT-PCR, flow, Luciferase reporter assay, Western blot	20375304
MIRT000711	hsa-miR-146a-5p	qRT-PCR	18759964
MIRT000711	hsa-miR-146a-5p	Immunoprecipitaion, Western blot, Communoprecipitaion	19898489
MIRT000711	hsa-miR-146a-5p	qRT-PCR, Western blot, Immunofluorescence	19918258
MIRT000711	hsa-miR-146a-5p	Luciferase reporter assay, Microarray, Northern blot, qRT-PCR	16885212
MIRT000711	hsa-miR-146a-5p	ELISA, Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	20542134
MIRT000711	hsa-miR-146a-5p	qRT-PCR, Western blot	21178010
MIRT000711	hsa-miR-146a-5p	Luciferase reporter assay, qRT-PCR, Western blot	21610143
MIRT000711	hsa-miR-146a-5p	Luciferase reporter assay	22593544
MIRT000711	hsa-miR-146a-5p	Western blot	20110513
MIRT000711	hsa-miR-146a-5p	Luciferase reporter assay	24107356
MIRT000711	hsa-miR-146a-5p	Microarray	25205119
MIRT000711	hsa-miR-146a-5p	ELISA, Northern blot, Western blot	23685241
MIRT000711	hsa-miR-146a-5p	Next Generation Sequencing (NGS), Northern blot, pSILAC	26151128
MIRT000711	hsa-miR-146a-5p	qRT-PCR, Western blot	25889446
MIRT000711	hsa-miR-146a-5p	Immunohistochemistry, Luciferase reporter assay, qRT-PCR, Western blot	27904767
MIRT005394	hsa-miR-146b-5p	Luciferase reporter assay, Microarray, Northern blot, qRT-PCR	16885212
MIRT005394	hsa-miR-146b-5p	Immunohistochemistry, In situ hybridization, Luciferase reporter assay, qRT-PCR, Western blot	26320176
MIRT130042	hsa-miR-1253	PAR-CLIP	23592263
MIRT130055	hsa-miR-5197-3p	PAR-CLIP	23592263
MIRT383128	hsa-miR-5692a	PAR-CLIP	22100165
MIRT383129	hsa-miR-410-3p	PAR-CLIP	22100165
MIRT438046	hsa-miR-125a-5p	Luciferase reporter assay, qRT-PCR, Western blot	24360988
MIRT439396	hsa-miR-374a-5p	HITS-CLIP	22473208
MIRT449126	hsa-miR-1304-5p	PAR-CLIP	22100165
MIRT449127	hsa-miR-6083	PAR-CLIP	22100165
MIRT449128	hsa-miR-6869-5p	PAR-CLIP	22100165
MIRT449129	hsa-miR-6765-5p	PAR-CLIP	22100165
MIRT449130	hsa-miR-190a-3p	PAR-CLIP	22100165
MIRT449131	hsa-miR-633	PAR-CLIP	22100165
MIRT449132	hsa-miR-1827	PAR-CLIP	22100165
MIRT449133	hsa-miR-3163	PAR-CLIP	22100165
MIRT482792	hsa-miR-3202	PAR-CLIP	23592263
MIRT482793	hsa-miR-6763-5p	PAR-CLIP	23592263
MIRT482794	hsa-miR-6748-5p	PAR-CLIP	23592263
MIRT482795	hsa-miR-3150a-3p	PAR-CLIP	23592263
MIRT482796	hsa-miR-491-5p	PAR-CLIP	23592263
MIRT482797	hsa-miR-6769b-5p	PAR-CLIP	23592263
MIRT482798	hsa-miR-6769a-5p	PAR-CLIP	23592263
MIRT482799	hsa-miR-92a-2-5p	PAR-CLIP	23592263
MIRT482800	hsa-miR-4483	PAR-CLIP	23592263
MIRT482801	hsa-miR-1293	PAR-CLIP	23592263
MIRT482802	hsa-miR-6766-5p	PAR-CLIP	23592263
MIRT482803	hsa-miR-6745	PAR-CLIP	23592263
MIRT482804	hsa-miR-6756-5p	PAR-CLIP	23592263
MIRT482805	hsa-miR-363-5p	PAR-CLIP	23592263
MIRT482806	hsa-miR-6825-5p	PAR-CLIP	23592263
MIRT482807	hsa-miR-939-5p	PAR-CLIP	23592263
MIRT482808	hsa-miR-1343-5p	PAR-CLIP	23592263
MIRT482809	hsa-miR-3175	PAR-CLIP	23592263
MIRT482810	hsa-miR-6883-5p	PAR-CLIP	23592263
MIRT482811	hsa-miR-6785-5p	PAR-CLIP	23592263
MIRT482812	hsa-miR-4728-5p	PAR-CLIP	23592263
MIRT482813	hsa-miR-6878-5p	PAR-CLIP	23592263
MIRT482814	hsa-miR-149-3p	PAR-CLIP	23592263
MIRT482815	hsa-miR-6797-5p	PAR-CLIP	23592263
MIRT482816	hsa-miR-1249-5p	PAR-CLIP	23592263
MIRT482817	hsa-miR-5703	PAR-CLIP	23592263
MIRT482818	hsa-miR-4516	PAR-CLIP	23592263
MIRT482819	hsa-miR-4434	PAR-CLIP	23592263
MIRT482820	hsa-miR-6133	PAR-CLIP	23592263
MIRT482821	hsa-miR-6130	PAR-CLIP	23592263
MIRT482822	hsa-miR-6127	PAR-CLIP	23592263
MIRT482823	hsa-miR-6129	PAR-CLIP	23592263
MIRT482824	hsa-miR-4510	PAR-CLIP	23592263
MIRT482825	hsa-miR-4419a	PAR-CLIP	23592263
MIRT482826	hsa-miR-6760-5p	PAR-CLIP	23592263
MIRT565226	hsa-miR-6516-5p	PAR-CLIP	20371350
MIRT565226	hsa-miR-6516-5p	PAR-CLIP	26701625
MIRT565227	hsa-miR-455-3p	PAR-CLIP	20371350
MIRT565227	hsa-miR-455-3p	PAR-CLIP	26701625
MIRT565228	hsa-miR-6807-5p	PAR-CLIP	20371350
MIRT565228	hsa-miR-6807-5p	PAR-CLIP	26701625
MIRT565229	hsa-miR-7847-3p	PAR-CLIP	20371350
MIRT565229	hsa-miR-7847-3p	PAR-CLIP	26701625
MIRT565230	hsa-miR-6880-5p	PAR-CLIP	20371350
MIRT565230	hsa-miR-6880-5p	PAR-CLIP	26701625
MIRT565231	hsa-miR-6799-5p	PAR-CLIP	20371350
MIRT565231	hsa-miR-6799-5p	PAR-CLIP	26701625
MIRT565232	hsa-miR-6851-5p	PAR-CLIP	20371350
MIRT565232	hsa-miR-6851-5p	PAR-CLIP	26701625
MIRT565233	hsa-miR-3689d	PAR-CLIP	20371350
MIRT565233	hsa-miR-3689d	PAR-CLIP	26701625
MIRT565234	hsa-miR-6499-3p	PAR-CLIP	20371350
MIRT565234	hsa-miR-6499-3p	PAR-CLIP	26701625
MIRT565235	hsa-miR-6086	PAR-CLIP	20371350
MIRT565235	hsa-miR-6086	PAR-CLIP	26701625
MIRT565236	hsa-miR-377-5p	PAR-CLIP	20371350
MIRT565236	hsa-miR-377-5p	PAR-CLIP	26701625
MIRT565237	hsa-miR-6134	PAR-CLIP	20371350
MIRT565237	hsa-miR-6134	PAR-CLIP	26701625
MIRT565238	hsa-miR-1233-3p	PAR-CLIP	20371350
MIRT565238	hsa-miR-1233-3p	PAR-CLIP	26701625
MIRT565239	hsa-miR-1225-3p	PAR-CLIP	20371350
MIRT565239	hsa-miR-1225-3p	PAR-CLIP	26701625
MIRT565240	hsa-miR-1247-3p	PAR-CLIP	20371350
MIRT565240	hsa-miR-1247-3p	PAR-CLIP	26701625
MIRT565241	hsa-miR-3940-3p	PAR-CLIP	20371350
MIRT565241	hsa-miR-3940-3p	PAR-CLIP	26701625
MIRT737514	hsa-miR-135a-5p	PAR-CLIP	26701625
MIRT737518	hsa-miR-135b-5p	PAR-CLIP	26701625
MIRT746114	hsa-miR-4537	PAR-CLIP	26701625
MIRT749468	hsa-miR-500a-3p	PAR-CLIP	26701625

Transcription factors

Transcription factor	Regulation	Reference
RUNX3	Activation	17956589

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IMP	18093978
GO:0000187	Process	Activation of MAPK activity	TAS
GO:0000209	Process	Protein polyubiquitination	IDA	15125833, 19675569
GO:0001503	Process	Ossification	IEA
GO:0001701	Process	In utero embryonic development	IEA
GO:0001843	Process	Neural tube closure	IEA
GO:0002223	Process	Stimulatory C-type lectin receptor signaling pathway	TAS
GO:0002224	Process	Toll-like receptor signaling pathway	TAS
GO:0002637	Process	Regulation of immunoglobulin production	IEA
GO:0002726	Process	Positive regulation of T cell cytokine production	IMP	15125833
GO:0002755	Process	MyD88-dependent toll-like receptor signaling pathway	TAS
GO:0004842	Function	Ubiquitin-protein transferase activity	EXP	15361868, 17135271
GO:0004842	Function	Ubiquitin-protein transferase activity	IBA	21873635
GO:0004842	Function	Ubiquitin-protein transferase activity	TAS
GO:0005164	Function	Tumor necrosis factor receptor binding	IBA	21873635
GO:0005164	Function	Tumor necrosis factor receptor binding	IPI	11728344
GO:0005515	Function	Protein binding	IPI	10094049, 10465784, 10514511, 10920205, 11238466, 11244088, 11279055, 11397809, 11463333, 11518704, 11751921, 12140561, 12242293, 12270937, 12459498, 12496252, 12925853, 14982987, 15121867, 15125833, 15280356, 15998638, 16189514, 16286467, 16378096, 16874300, 16932746, 17124500, 173
GO:0005634	Component	Nucleus	IDA	18093978
GO:0005737	Component	Cytoplasm	IDA	16378096, 18093978
GO:0005811	Component	Lipid droplet	ISS
GO:0005829	Component	Cytosol	TAS
GO:0005886	Component	Plasma membrane	IDA	18093978
GO:0005886	Component	Plasma membrane	TAS
GO:0005938	Component	Cell cortex	IEA
GO:0006974	Process	Cellular response to DNA damage stimulus	IEA
GO:0007249	Process	I-kappaB kinase/NF-kappaB signaling	TAS
GO:0007250	Process	Activation of NF-kappaB-inducing kinase activity	IMP	15125833
GO:0007254	Process	JNK cascade	TAS
GO:0008270	Function	Zinc ion binding	IEA
GO:0009898	Component	Cytoplasmic side of plasma membrane	ISS
GO:0010008	Component	Endosome membrane	TAS
GO:0016579	Process	Protein deubiquitination	TAS
GO:0019886	Process	Antigen processing and presentation of exogenous peptide antigen via MHC class II	IEA
GO:0019901	Function	Protein kinase binding	IPI	19713527
GO:0030316	Process	Osteoclast differentiation	IEA
GO:0031293	Process	Membrane protein intracellular domain proteolysis	TAS
GO:0031398	Process	Positive regulation of protein ubiquitination	NAS	22412986
GO:0031435	Function	Mitogen-activated protein kinase kinase kinase binding	IPI	10094049
GO:0031624	Function	Ubiquitin conjugating enzyme binding	IDA	23776175
GO:0031625	Function	Ubiquitin protein ligase binding	IPI	11279055
GO:0031666	Process	Positive regulation of lipopolysaccharide-mediated signaling pathway	IEA
GO:0031996	Function	Thioesterase binding	IPI	11279055
GO:0032147	Process	Activation of protein kinase activity	IDA	17135271
GO:0032735	Process	Positive regulation of interleukin-12 production	IEA
GO:0032743	Process	Positive regulation of interleukin-2 production	IMP	15125833
GO:0032755	Process	Positive regulation of interleukin-6 production	IEA
GO:0032991	Component	Protein-containing complex	IDA	23776175
GO:0033209	Process	Tumor necrosis factor-mediated signaling pathway	IBA	21873635
GO:0034162	Process	Toll-like receptor 9 signaling pathway	TAS
GO:0035631	Component	CD40 receptor complex	ISS
GO:0038095	Process	Fc-epsilon receptor signaling pathway	TAS
GO:0042088	Process	T-helper 1 type immune response	IEA
GO:0042102	Process	Positive regulation of T cell proliferation	IEA
GO:0042475	Process	Odontogenesis of dentin-containing tooth	IEA
GO:0042802	Function	Identical protein binding	IPI	19465916, 21988832, 22493164, 25416956, 27107012, 32296183
GO:0042826	Function	Histone deacetylase binding	IPI	18093978
GO:0043011	Process	Myeloid dendritic cell differentiation	IEA
GO:0043065	Process	Positive regulation of apoptotic process	TAS
GO:0043066	Process	Negative regulation of apoptotic process	TAS
GO:0043122	Process	Regulation of I-kappaB kinase/NF-kappaB signaling	IBA	21873635
GO:0043123	Process	Positive regulation of I-kappaB kinase/NF-kappaB signaling	IDA	17135271
GO:0043123	Process	Positive regulation of I-kappaB kinase/NF-kappaB signaling	TAS
GO:0043422	Function	Protein kinase B binding	IPI	19713527
GO:0043507	Process	Positive regulation of JUN kinase activity	IDA	11751921
GO:0043507	Process	Positive regulation of JUN kinase activity	NAS	17135271
GO:0045453	Process	Bone resorption	IEA
GO:0045672	Process	Positive regulation of osteoclast differentiation	IDA	17135271
GO:0045892	Process	Negative regulation of transcription, DNA-templated	IMP	18093978
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IDA	11751921
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	NAS	22412986
GO:0046330	Process	Positive regulation of JNK cascade	IBA	21873635
GO:0047485	Function	Protein N-terminus binding	IPI	14530355
GO:0048468	Process	Cell development	IEA
GO:0048471	Component	Perinuclear region of cytoplasm	IDA	11751921
GO:0048661	Process	Positive regulation of smooth muscle cell proliferation	IEA
GO:0050852	Process	T cell receptor signaling pathway	IMP	15125833
GO:0050852	Process	T cell receptor signaling pathway	TAS
GO:0051091	Process	Positive regulation of DNA-binding transcription factor activity	IMP	12296995
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	IDA	11279055, 11751921, 16378096
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	IMP	12296995
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	TAS
GO:0051865	Process	Protein autoubiquitination	IDA	17135271, 18093978, 23776175
GO:0051865	Process	Protein autoubiquitination	TAS	16378096
GO:0061630	Function	Ubiquitin protein ligase activity	IDA	15125833, 17135271, 19713527
GO:0070423	Process	Nucleotide-binding oligomerization domain containing signaling pathway	TAS
GO:0070498	Process	Interleukin-1-mediated signaling pathway	IBA	21873635
GO:0070498	Process	Interleukin-1-mediated signaling pathway	TAS
GO:0070534	Process	Protein K63-linked ubiquitination	IBA	21873635
GO:0070534	Process	Protein K63-linked ubiquitination	IDA	19713527, 21068390
GO:0070534	Process	Protein K63-linked ubiquitination	IGI	17135271, 19675569
GO:0070555	Process	Response to interleukin-1	IDA	17135271
GO:0071222	Process	Cellular response to lipopolysaccharide	IDA	23776175
GO:0071345	Process	Cellular response to cytokine stimulus	IMP	25515214
GO:0098802	Component	Plasma membrane signaling receptor complex	IBA	21873635
GO:1901224	Process	Positive regulation of NIK/NF-kappaB signaling	IMP	25515214
GO:1904996	Process	Positive regulation of leukocyte adhesion to vascular endothelial cell	IMP	25515214
GO:2000679	Process	Positive regulation of transcription regulatory region DNA binding	IDA	11751921

Other IDs

• MIM: 602355
• HGNC: 12036
• e!Ensembl: ENSG00000175104

Protein

• UniProt ID: Q9Y4K3
• Protein name: TNF receptor-associated factor 6 (EC 2.3.2.27) (E3 ubiquitin-protein ligase TRAF6) (Interleukin-1 signal transducer) (RING finger protein 85) (RING-type E3 ubiquitin transferase TRAF6)
• Protein function: E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production.
• PDB: 1LB4, 1LB5, 1LB6, 2ECI, 2JMD, 3HCS, 3HCT, 3HCU, 4Z8M, 5ZUJ, 6A33, 7L3L
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF13923	zf-C3HC4_2	69 → 107		Domain
  PF18048	TRAF6_Z2	157 → 183	TNF receptor-associated factor 6 zinc finger 2	Domain
  PF02176	zf-TRAF	204 → 261	TRAF-type zinc finger	Family

• Sequence:

  MSLLNCENSCGSSQSESDCCVAMASSCSAVTKDDSVGGTASTGNLSSSFMEEIQGYDVEF
  DPPLESKYECPICLMALREAVQTPCGHRFCKACIIKSIRDAGHKCPVDNEILLENQLFPD
  NFAKREILSLMVKCPNEGCLHKMELRHLEDHQAHCEFALMDCPQCQRPFQKFHINIHILK
  DCPRRQVSCDNCAASMAFEDKEIHDQNCPLANVICEYCNTILIREQMPNHYDLDCPTAPI
  PCTFSTFGCHEKMQRNHLARHLQENTQSHMRMLAQAVHSLSVIPDSGYISEVRNFQETIH
  QLEGRLVRQDHQIRELTAKMETQSMYVSELKRTIRTLEDKVAEIEAQQCNGIYIWKIGNF
  GMHLKCQEEEKPVVIHSPGFYTGKPGYKLCMRLHLQLPTAQRCANYISLFVHTMQGEYDS
  HLPWPFQGTIRLTILDQSEAPVRQNHEEIMDAKPELLAFQRPTIPRNPKGFGYVTFMHLE
  ALRQRTFIKDDTLLVRCEVSTRFDMGSLRREGFQPRSTDAGV

• Sequence length: 522