TRAF2_MOUSE
ID TRAF2_MOUSE Reviewed; 501 AA.
AC P39429; A2AJA3; O54896;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=TNF receptor-associated factor 2;
DE EC=2.3.2.27;
DE AltName: Full=E3 ubiquitin-protein ligase TRAF2;
DE AltName: Full=RING-type E3 ubiquitin transferase TRAF2 {ECO:0000305};
GN Name=Traf2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INTERACTION WITH TRAF1 AND
RP TNFRSF1B.
RX PubMed=8069916; DOI=10.1016/0092-8674(94)90532-0;
RA Rothe M., Wong S.C., Henzel W.J., Goeddel D.V.;
RT "A novel family of putative signal transducers associated with the
RT cytoplasmic domain of the 75 kDa tumor necrosis factor receptor.";
RL Cell 78:681-692(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J; TISSUE=Kidney;
RX PubMed=9461607; DOI=10.1074/jbc.273.7.4129;
RA Brink R., Lodish H.F.;
RT "Tumor necrosis factor receptor (TNFR)-associated factor 2A (TRAF2A), a
RT TRAF2 splice variant with an extended RING finger domain that inhibits
RT TNFR2-mediated NF-kappaB activation.";
RL J. Biol. Chem. 273:4129-4134(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE (ISOFORM 1).
RC STRAIN=C57BL/6J;
RX PubMed=11275257; DOI=10.1016/s0161-5890(00)00098-5;
RA Grech A., Quinn R., Srinivasan D., Badoux X., Brink R.;
RT "Complete structural characterisation of the mammalian and Drosophila TRAF
RT genes: implications for TRAF evolution and the role of RING finger splice
RT variants.";
RL Mol. Immunol. 37:721-734(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=Czech II; TISSUE=Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 430-440, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=OF1; TISSUE=Hippocampus;
RA Lubec G., Sunyer B., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [7]
RP INTERACTION WITH TRADD.
RX PubMed=8565075; DOI=10.1016/s0092-8674(00)80984-8;
RA Hsu H., Shu H.-B., Pan M.G., Goeddel D.V.;
RT "TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1
RT signal transduction pathways.";
RL Cell 84:299-308(1996).
RN [8]
RP INTERACTION WITH TNFAIP3.
RX PubMed=8692885; DOI=10.1073/pnas.93.13.6721;
RA Song H.Y., Rothe M., Goeddel D.V.;
RT "The tumor necrosis factor-inducible zinc finger protein A20 interacts with
RT TRAF1/TRAF2 and inhibits NF-kappaB activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:6721-6725(1996).
RN [9]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=9390694; DOI=10.1016/s1074-7613(00)80391-x;
RA Yeh W.C., Shahinian A., Speiser D., Kraunus J., Billia F., Wakeham A.,
RA de la Pompa J.L., Ferrick D., Hum B., Iscove N., Ohashi P., Rothe M.,
RA Goeddel D.V., Mak T.W.;
RT "Early lethality, functional NF-kappaB activation, and increased
RT sensitivity to TNF-induced cell death in TRAF2-deficient mice.";
RL Immunity 7:715-725(1997).
RN [10]
RP INTERACTION WITH PEG3.
RX PubMed=9500555; DOI=10.1038/ng0398-287;
RA Relaix F., Wei X.-J., Wu X., Sassoon D.A.;
RT "Peg3/Pw1 is an imprinted gene involved in the TNF-NFkappaB signal
RT transduction pathway.";
RL Nat. Genet. 18:287-291(1998).
RN [11]
RP IDENTIFICATION IN A COMPLEX WITH TNFRSF8; TNFRSF1B, TRAF1 AND TRAIP, AND
RP INTERACTION WITH TRAIP.
RX PubMed=9104814; DOI=10.1084/jem.185.7.1275;
RA Lee S.Y., Lee S.Y., Choi Y.;
RT "TRAF-interacting protein (TRIP): a novel component of the tumor necrosis
RT factor receptor (TNFR)- and CD30-TRAF signaling complexes that inhibits
RT TRAF2-mediated NF-kappaB activation.";
RL J. Exp. Med. 185:1275-1285(1997).
RN [12]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=10514016; DOI=10.1016/s1074-7613(00)80113-2;
RA Nguyen L.T., Duncan G.S., Mirtsos C., Ng M., Speiser D.E., Shahinian A.,
RA Marino M.W., Mak T.W., Ohashi P.S., Yeh W.C.;
RT "TRAF2 deficiency results in hyperactivity of certain TNFR1 signals and
RT impairment of CD40-mediated responses.";
RL Immunity 11:379-389(1999).
RN [13]
RP INTERACTION WITH CASP8AP2.
RX PubMed=11340079; DOI=10.1074/jbc.m102941200;
RA Choi Y.-H., Kim K.-B., Kim H.-H., Hong G.-S., Kwon Y.-K., Chung C.-W.,
RA Park Y.-M., Shen Z.-J., Kim B.J., Lee S.-Y., Jung Y.-K.;
RT "FLASH coordinates NF-kappa B activity via TRAF2.";
RL J. Biol. Chem. 276:25073-25077(2001).
RN [14]
RP INTERACTION WITH NFATC2IP.
RX PubMed=11435475; DOI=10.1084/jem.194.1.89;
RA Lieberson R., Mowen K.A., McBride K.D., Leautaud V., Zhang X., Suh W.-K.,
RA Wu L., Glimcher L.H.;
RT "Tumor necrosis factor receptor-associated factor (TRAF)2 represses the T
RT helper cell type 2 response through interaction with NFAT-interacting
RT protein (NIP45).";
RL J. Exp. Med. 194:89-98(2001).
RN [15]
RP AUTOUBIQUITINATION, DEGRADATION, INTERACTION WITH CD40, AND MUTAGENESIS OF
RP CYS-34.
RX PubMed=11909853; DOI=10.1074/jbc.m111522200;
RA Brown K.D., Hostager B.S., Bishop G.A.;
RT "Regulation of TRAF2 signaling by self-induced degradation.";
RL J. Biol. Chem. 277:19433-19438(2002).
RN [16]
RP INTERACTION WITH HIVEP3.
RX PubMed=11804591; DOI=10.1016/s1097-2765(01)00434-8;
RA Oukka M., Kim S.T., Lugo G., Sun J., Wu L.-C., Glimcher L.H.;
RT "A mammalian homolog of Drosophila schnurri, KRC, regulates TNF receptor-
RT driven responses and interacts with TRAF2.";
RL Mol. Cell 9:121-131(2002).
RN [17]
RP FUNCTION.
RX PubMed=15175328; DOI=10.1074/jbc.m404206200;
RA Lee T.H., Shank J., Cusson N., Kelliher M.A.;
RT "The kinase activity of Rip1 is not required for tumor necrosis factor-
RT alpha-induced IkappaB kinase or p38 MAP kinase activation or for the
RT ubiquitination of Rip1 by Traf2.";
RL J. Biol. Chem. 279:33185-33191(2004).
RN [18]
RP FUNCTION.
RX PubMed=15121867; DOI=10.1128/mcb.24.10.4502-4512.2004;
RA Gil J., Garcia M.A., Gomez-Puertas P., Guerra S., Rullas J., Nakano H.,
RA Alcami J., Esteban M.;
RT "TRAF family proteins link PKR with NF-kappa B activation.";
RL Mol. Cell. Biol. 24:4502-4512(2004).
RN [19]
RP INTERACTION WITH TRPC4AP.
RX PubMed=16876162; DOI=10.1016/j.febslet.2006.06.098;
RA Soond S.M., Terry J.L., Riches D.W.H.;
RT "TRUSS, a tumor necrosis factor receptor-1-interacting protein, activates
RT c-Jun NH(2)-terminal kinase and transcription factor AP-1.";
RL FEBS Lett. 580:4591-4596(2006).
RN [20]
RP INTERACTION WITH DAB2IP AND ERN1.
RX PubMed=18281285; DOI=10.1074/jbc.m710557200;
RA Luo D., He Y., Zhang H., Yu L., Chen H., Xu Z., Tang S., Urano F., Min W.;
RT "AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress
RT response.";
RL J. Biol. Chem. 283:11905-11912(2008).
RN [21]
RP INTERACTION WITH TRAFD1.
RX PubMed=18849341; DOI=10.1074/jbc.m806923200;
RA Sanada T., Takaesu G., Mashima R., Yoshida R., Kobayashi T., Yoshimura A.;
RT "FLN29 deficiency reveals its negative regulatory role in the Toll-like
RT receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicase
RT signaling pathway.";
RL J. Biol. Chem. 283:33858-33864(2008).
RN [22]
RP FUNCTION, DISRUPTION PHENOTYPE, AND IDENTIFICATION IN A COMPLEX WITH
RP MAP3K14; BIRC3 AND TRAF3.
RX PubMed=18997792; DOI=10.1038/ni.1678;
RA Vallabhapurapu S., Matsuzawa A., Zhang W., Tseng P.H., Keats J.J., Wang H.,
RA Vignali D.A., Bergsagel P.L., Karin M.;
RT "Nonredundant and complementary functions of TRAF2 and TRAF3 in a
RT ubiquitination cascade that activates NIK-dependent alternative NF-kappaB
RT signaling.";
RL Nat. Immunol. 9:1364-1370(2008).
RN [23]
RP FUNCTION, AND IDENTIFICATION IN A COMPLEX WITH TRAF3; BIRC2 AND BIRC3.
RX PubMed=18997794; DOI=10.1038/ni.1676;
RA Zarnegar B.J., Wang Y., Mahoney D.J., Dempsey P.W., Cheung H.H., He J.,
RA Shiba T., Yang X., Yeh W.C., Mak T.W., Korneluk R.G., Cheng G.;
RT "Noncanonical NF-kappaB activation requires coordinated assembly of a
RT regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the
RT kinase NIK.";
RL Nat. Immunol. 9:1371-1378(2008).
RN [24]
RP FUNCTION, IDENTIFICATION IN COMPLEX I; INTERACTION WITH TAK1; IKKA; IKKB;
RP TAB2 AND TAB3, AND PHOSPHORYLATION AT THR-117.
RX PubMed=19150425; DOI=10.1016/j.molcel.2008.11.023;
RA Li S., Wang L., Dorf M.E.;
RT "PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-
RT linked polyubiquitination.";
RL Mol. Cell 33:30-42(2009).
RN [25]
RP INTERACTION WITH BIRC2.
RX PubMed=19506082; DOI=10.1074/jbc.m109.029983;
RA Csomos R.A., Brady G.F., Duckett C.S.;
RT "Enhanced cytoprotective effects of the inhibitor of apoptosis protein
RT cellular IAP1 through stabilization with TRAF2.";
RL J. Biol. Chem. 284:20531-20539(2009).
RN [26]
RP FUNCTION, IDENTIFICATION IN COMPLEX I, DOMAIN, AND MUTAGENESIS OF GLU-283;
RP GLU-292 AND GLU-294.
RX PubMed=19815541; DOI=10.1074/jbc.m109.072256;
RA Vince J.E., Pantaki D., Feltham R., Mace P.D., Cordier S.M., Schmukle A.C.,
RA Davidson A.J., Callus B.A., Wong W.W., Gentle I.E., Carter H., Lee E.F.,
RA Walczak H., Day C.L., Vaux D.L., Silke J.;
RT "TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis
RT factor (TNF) to efficiently activate NF-{kappa}B and to prevent TNF-induced
RT apoptosis.";
RL J. Biol. Chem. 284:35906-35915(2009).
RN [27]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=19409903; DOI=10.1016/j.jmb.2009.04.054;
RA Zhang L., Blackwell K., Thomas G.S., Sun S., Yeh W.C., Habelhah H.;
RT "TRAF2 suppresses basal IKK activity in resting cells and TNFalpha can
RT activate IKK in TRAF2 and TRAF5 double knockout cells.";
RL J. Mol. Biol. 389:495-510(2009).
RN [28]
RP INTERACTION WITH TNFAIP3 AND TAX1BP1.
RX PubMed=20185725; DOI=10.1126/science.1182364;
RA Shembade N., Ma A., Harhaj E.W.;
RT "Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin
RT enzyme complexes.";
RL Science 327:1135-1139(2010).
RN [29]
RP INTERACTION WITH UXT.
RX PubMed=21307340; DOI=10.1091/mbc.e10-10-0827;
RA Huang Y., Chen L., Zhou Y., Liu H., Yang J., Liu Z., Wang C.;
RT "UXT-V1 protects cells against TNF-induced apoptosis through modulating
RT complex II formation.";
RL Mol. Biol. Cell 22:1389-1397(2011).
RN [30]
RP INTERACTION WITH GPS2.
RX PubMed=22424771; DOI=10.1016/j.molcel.2012.01.025;
RA Cardamone M.D., Krones A., Tanasa B., Taylor H., Ricci L., Ohgi K.A.,
RA Glass C.K., Rosenfeld M.G., Perissi V.;
RT "A protective strategy against hyperinflammatory responses requiring the
RT nontranscriptional actions of GPS2.";
RL Mol. Cell 46:91-104(2012).
RN [31]
RP UBIQUITINATION.
RX PubMed=25026888; DOI=10.1038/ncomms5434;
RA Su X., Min S., Cao S., Yan H., Zhao Y., Li H., Chai L., Mei S., Yang J.,
RA Zhang Y., Zhang Z., Liu F., Sun W., Che Y., Yang R.;
RT "LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent
RT infection by uropathogenic bacteria.";
RL Nat. Commun. 5:4434-4434(2014).
CC -!- FUNCTION: Regulates activation of NF-kappa-B and JNK and plays a
CC central role in the regulation of cell survival and apoptosis. Required
CC for normal antibody isotype switching from IgM to IgG. Has E3
CC ubiquitin-protein ligase activity and promotes 'Lys-63'-linked
CC ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is
CC an essential constituent of several E3 ubiquitin-protein ligase
CC complexes, where it promotes the ubiquitination of target proteins by
CC bringing them into contact with other E3 ubiquitin ligases. Regulates
CC BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination
CC and subsequent degradation; this does not depend on the TRAF2 RING-type
CC zinc finger domain. Isoform 2 does not seem to mediate activation of
CC NF-kappa-B but inhibits isoform 1 activity. Plays a role in mediating
CC activation of NF-kappa-B by EIF2AK2/PKR. In complex with BIRC2 or
CC BIRC3, promotes ubiquitination of IKBKE. {ECO:0000269|PubMed:10514016,
CC ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15175328,
CC ECO:0000269|PubMed:18997792, ECO:0000269|PubMed:18997794,
CC ECO:0000269|PubMed:19409903, ECO:0000269|PubMed:19815541,
CC ECO:0000269|PubMed:9390694}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27;
CC -!- ACTIVITY REGULATION: Has very low E3 ubiquitin ligase activity in the
CC absence of sphingosine-1-phosphate. E3 ubiquitin ligase activity is
CC strongly activated by cytoplasmic sphingosine-1-phosphate.
CC {ECO:0000250|UniProtKB:Q12933}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Homotrimer (By similarity). Heterotrimer with TRAF1
CC (PubMed:8069916). Heterotrimer with TRAF3 (via TRAF domain) (By
CC similarity). The domain containing the RING-type and the first TRAF-
CC type zinc finger can also form homodimers (in vitro) (By similarity).
CC Interacts with TNFRSF1B/TNFR2 (PubMed:8069916). Interacts with
CC TNFRSF5/CD40 (PubMed:11909853). Interacts with TNFRSF4, TNFRSF7/CD27,
CC TNFRSF8/CD30, TNFRSF9/CD137, TNFRSF11A/RANK, TNFRSF13B/TACI, TNFRSF14,
CC TNFRSF16/NGFR, TNFRSF17/BCMA, TNFRSF18/AITR, TNFRSF19/TROY,
CC TNFRSF19L/RELT and EDAR (By similarity). Stimulation of TNF-alpha
CC receptor TNFRSF1A leads to the formation of two distinct signaling
CC complexes. Plasma membrane-bound complex I is composed of TNFRSF1A,
CC TRADD, RIPK1, TRAF2 and BIRC2/c-IAP1 or BIRC3 which interacts with
CC CHUCK/IKK-alpha, IKBKB/IKK-beta and IKBKG/IKK-gamma promoting cell
CC survival (PubMed:19150425, PubMed:19815541). Subsequently, TRADD, RIPK1
CC and TRAF2 dissociate from TNFRSF1A and form cytoplasmic complex II with
CC FADD and caspase CASP8 promoting cell apoptosis (By similarity).
CC Interacts with TRADD (PubMed:8565075). Identified in a complex with
CC TNFRSF1A, RIPK1 and IKBKB/IKK-beta (By similarity). Interacts with
CC RIPK2 (By similarity). Interacts with BIRC2 and BIRC3 N-terminus; a
CC single BIRC2 or BIRC3 molecule interacts with a heterotrimer formed by
CC TRAF1 and TRAF2, or a TRAF2 homotrimer (By similarity). Identified in a
CC complex composed of TRAF2, TRAF3, BIRC2 and BIRC3 (PubMed:18997794).
CC Interacts with BIRC2; the interaction promotes BIRC2 stability
CC (PubMed:19506082). Interaction with BIRC2 and/or BIRC3 is essential for
CC ubiquitination of IKBKE, degradation of NFKBIA and activation of NF-
CC kappa-B (PubMed:19815541). Within complex I, phosphorylated TRAF2
CC interacts (via 'Lys-63'-linked polyubiquitin chains) with CHUCK/IKK-
CC alpha, IKBKB/IKK-beta, IKBKG/IKK-gamma TAB2, TAB3 and TAK1 in response
CC to TNF-alpha stimulation (PubMed:19150425). Within complex I, interacts
CC with UXT isoform 1 (via TPQE motif); the interaction prevents the
CC recruitment of FADD and CASP8/caspase 8 to complex I (PubMed:21307340).
CC Forms a complex composed of TNFRSF8/CD30 or TNFRSF1B/TNFR2, and TRAF1,
CC TRAF2 and E3 ligase TRAIP (PubMed:9104814). Within the complex,
CC interacts with TRAIP; the interaction inhibits TRAF2-mediated NF-kappa
CC B activation (PubMed:9104814). Component of a complex composed of TANK
CC and TBK1 (By similarity). Interacts with TRPC4AP (PubMed:16876162).
CC Interacts with MAP3K1/MEKK1, MAP3K5/ASK1 and MAP3K11/MLK3 in response
CC to TNF-alpha stimulation; the interaction leads to JNK activation and
CC interaction with MAP3K5 is inhibited by PRMT1 (By similarity).
CC Component of a complex composed of MAP3K14/NIK BIRC3 and TRAF3; the
CC interaction leads to BIRC2/3-mediated ubiquitination of TRAF3 upon CD40
CC engagement in a TRAF2-dependent manner (PubMed:18997792). Interacts
CC with MAP3K14/NIK in response to TNF-alpha stimulation; the interaction
CC leads to NF-kappa B activation (By similarity). Interacts with PEG3;
CC the interaction may promote TRAF2-mediated NF-kappa B activation
CC (PubMed:9500555). Interacts with HIVEP3; the interaction may inhibit
CC TNF-alpha-TRAF2-mediated NF-kappa B and JNK activation
CC (PubMed:11804591). Interacts with TANK/ITRAF; the interaction prevents
CC interaction between TNFRSF1B/TNFR2 and TRAF2 (By similarity). Interacts
CC with deubiquitinating enzyme CYLD; the interaction results in the
CC deubiquitination and inactivation of TRAF2 (By similarity). Interacts
CC with SIAH2; the interaction leads to TRAF2 ubiquitination and
CC degradation (By similarity). Interacts with E2 conjugating enzyme
CC UBE2N/Ubc13, E3 ligase ITCH and RNF11 in response to TNF-alpha
CC stimulation (By similarity). Interacts with ubiquitin-editing enzyme
CC TNFAIP3/A20 in response to TNF-alpha stimulation; the interaction
CC promotes TRAF2 dissociation from UBE2N/Ubc13, ITCH, RNF11 and TAX1BP1
CC and prevents prolonged TRAF-2 ubiquitination (PubMed:8692885,
CC PubMed:20185725). Interacts with TAX1BP1 in response to TNF-alpha
CC stimulation; the interaction promotes TRAF2 dissociation from
CC UBE2N/Ubc13 and TNFAIP3/A20, and prevents prolonged TRAF-2
CC ubiquitination (PubMed:20185725). Interacts (via C-terminus) with
CC EIF2AK2/PKR (via the kinase catalytic domain) (By similarity).
CC Interacts with deubiquitinating enzyme USP48 (By similarity). Interacts
CC with PTPN2; probably involved in TNF-mediated signaling (By
CC similarity). Interacts with Toll-like receptor TLR4/3 adapter
CC TICAM1/TRIF; the interaction may promote TICAM1 ubiquitination (By
CC similarity). Interacts with kinase/endoribonuclease ERN1/IRE1 and
CC DAB2IP in response to ER stress; the interaction requires DAB2IP
CC (PubMed:18281285). Interacts with ERN1/IRE1 and TAOK3 in response to ER
CC stress; the interaction may promote TRAF2 phosphorylation (By
CC similarity). Interacts (via zinc fingers) with DAB2IP (via C-terminus
CC PER domain) in response to TNF-alpha stimulation (By similarity).
CC Interacts with CASP8AP2/FLASH (PubMed:11340079). Interacts with
CC NFATC2IP; the interaction may repress IL-4 production in T cells
CC (PubMed:11435475). Interacts with kinase CDK9. Interacts with
CC sphingosine kinase 1 SPHK1 (By similarity). Interacts with kinase TNIK
CC (By similarity). Interacts with TRAFD1 (PubMed:18849341). Interacts
CC with DNA phosphodiesterase TDP2 (By similarity). Interacts with
CC MAVS/IPS1. Interacts with CARD14 (By similarity). Interacts with GPS2
CC (PubMed:22424771). Interacts with XPNPEP3 (By similarity). Interacts
CC with RIPK3 (By similarity). Interacts with RELL2 (By similarity).
CC Interacts with LRRC19 (By similarity). Interacts with GAPDH; promoting
CC TRAF2 ubiquitination (By similarity). {ECO:0000250|UniProtKB:Q12933,
CC ECO:0000269|PubMed:11340079, ECO:0000269|PubMed:11435475,
CC ECO:0000269|PubMed:11804591, ECO:0000269|PubMed:11909853,
CC ECO:0000269|PubMed:16876162, ECO:0000269|PubMed:18281285,
CC ECO:0000269|PubMed:18849341, ECO:0000269|PubMed:18997792,
CC ECO:0000269|PubMed:18997794, ECO:0000269|PubMed:19150425,
CC ECO:0000269|PubMed:19506082, ECO:0000269|PubMed:19815541,
CC ECO:0000269|PubMed:20185725, ECO:0000269|PubMed:21307340,
CC ECO:0000269|PubMed:22424771, ECO:0000269|PubMed:8069916,
CC ECO:0000269|PubMed:8565075, ECO:0000269|PubMed:8692885,
CC ECO:0000269|PubMed:9104814, ECO:0000269|PubMed:9500555}.
CC -!- INTERACTION:
CC P39429; O08863: Birc3; NbExp=7; IntAct=EBI-520016, EBI-642236;
CC P39429; P27512: Cd40; NbExp=3; IntAct=EBI-520016, EBI-525742;
CC P39429; Q920A9: Fcrla; NbExp=5; IntAct=EBI-520016, EBI-646587;
CC P39429; Q62406: Irak1; NbExp=2; IntAct=EBI-520016, EBI-448533;
CC P39429; P50284: Ltbr; NbExp=3; IntAct=EBI-520016, EBI-647023;
CC P39429; Q62073: Map3k7; NbExp=2; IntAct=EBI-520016, EBI-1775345;
CC P39429; Q8CDB0: Mknk2; NbExp=3; IntAct=EBI-520016, EBI-646209;
CC P39429; P70347-1: Tank; NbExp=7; IntAct=EBI-520016, EBI-646125;
CC P39429; Q60769: Tnfaip3; NbExp=3; IntAct=EBI-520016, EBI-646595;
CC P39429; O35305: Tnfrsf11a; NbExp=2; IntAct=EBI-520016, EBI-647362;
CC P39429; P47741: Tnfrsf4; NbExp=12; IntAct=EBI-520016, EBI-520001;
CC P39429; Q60803: Traf3; NbExp=2; IntAct=EBI-520016, EBI-520135;
CC P39429; PRO_0000037576 [P27958]; Xeno; NbExp=5; IntAct=EBI-520016, EBI-8753518;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P39429-1; Sequence=Displayed;
CC Name=2; Synonyms=TRAF2A;
CC IsoId=P39429-2; Sequence=VSP_007402;
CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 2 are expressed in spleen,
CC adipose tissues, skeletal muscles, thymus, testis, heart, lung, brain.
CC Isoform 2 is very weakly expressed in heart, lung and brain.
CC -!- DOMAIN: The coiled coil domain mediates homo- and hetero-
CC oligomerization. {ECO:0000269|PubMed:19815541}.
CC -!- DOMAIN: The MATH/TRAF domain binds to receptor cytoplasmic domains.
CC {ECO:0000269|PubMed:19815541}.
CC -!- DOMAIN: The RING-type zinc finger domain is essential for E3 ubiquitin-
CC protein ligase activity. It is not essential for the stabilization of
CC BIRC2, or for the ubiquitination of RIPK1 in response to TNFR1
CC signaling. {ECO:0000250|UniProtKB:Q12933}.
CC -!- PTM: Phosphorylated at several serine residues within the first 128
CC amino acid residues. Phosphorylated at Thr-117 in response to signaling
CC via TNF and TNFRSF1A. Phosphorylation at Thr-117 is required for 'Lys-
CC 63'-linked polyubiquitination, but not for 'Lys-48'-linked
CC polyubiquitination. Phosphorylation at Thr-117 is important for
CC interaction with IKKA and IKKB, activation of IKK and subsequent
CC activation of NF-kappa-B. {ECO:0000250|UniProtKB:Q12933}.
CC -!- PTM: Undergoes both 'Lys-48'-linked and 'Lys-63'-linked
CC polyubiquitination. Polyubiquitinated via 'Lys-63'-linked ubiquitin in
CC response to TNF signaling; this requires prior phosphorylation at Thr-
CC 117. 'Lys-63'-linked polyubiquitination promotes TRAF2-mediated
CC activation of NF-kappa-B. Can be polyubiquitinated at several Lys
CC residues via 'Lys-48'-linked ubiquitin chains in response to TNF
CC signaling, leading to proteasomal degradation. Autoubiquitinated,
CC leading to its subsequent proteasomal degradation. Polyubiquitinated by
CC BIRC2 and SIAH2, leading to its subsequent proteasomal degradation. Not
CC ubiquitinated by BIRC3 or SIAH1. Deubiquitinated by CYLD, a protease
CC that specifically cleaves 'Lys-63'-linked polyubiquitin chains.
CC Ubiquination is inhibited by LRRC19; inhiits proteasomal degradation
CC (PubMed:25026888). {ECO:0000250|UniProtKB:Q12933,
CC ECO:0000269|PubMed:25026888}.
CC -!- DISRUPTION PHENOTYPE: Important embryonic and perinatal mortality.
CC Life-born mutants appear normal at birth, but are smaller than their
CC littermates after three days, fail to thrive, and few survive more than
CC three weeks. Thymus and spleen are severely atrophic, and mice display
CC lymphopenia of both T and B lymphocytes, with normal erythrocyte
CC counts. Their thymocytes are abnormally sensitive to TNF-induced cell
CC death and exhibit high levels of spontaneous apoptosis. Macrophages are
CC highly sensitive to TNF and produce high levels of nitric oxide (NO) in
CC response to TNF. Likewise, endogenous TNF production is abnormally
CC increased upon exposure to TNF. Symptoms are much attenuated in mice
CC that are deficient for both Traf2 and Tnfrsf1a/Tnfr1, or Traf2 and Tnf.
CC Likewise, deletion of one Map3k14 allele alleviates symptoms and
CC rescues splenic atrophy and reduction of splenocyte numbers. Mice show
CC normal IgM production in response to viral infection, but lack CD40-
CC mediated proliferation of B-cells. They are deficient in antibody
CC isotype switching and fail to produce IgG.
CC {ECO:0000269|PubMed:10514016, ECO:0000269|PubMed:18997792,
CC ECO:0000269|PubMed:19409903, ECO:0000269|PubMed:9390694}.
CC -!- MISCELLANEOUS: [Isoform 2]: On mRNA level, has a significantly shorter
CC half-life than isoform 1. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the TNF receptor-associated factor family. A
CC subfamily. {ECO:0000305}.
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DR EMBL; L35303; AAC37662.1; -; mRNA.
DR EMBL; AF027570; AAC53545.1; -; mRNA.
DR EMBL; AF233332; AAF59928.1; -; Genomic_DNA.
DR EMBL; AF233326; AAF59928.1; JOINED; Genomic_DNA.
DR EMBL; AF233327; AAF59928.1; JOINED; Genomic_DNA.
DR EMBL; AF233328; AAF59928.1; JOINED; Genomic_DNA.
DR EMBL; AF233329; AAF59928.1; JOINED; Genomic_DNA.
DR EMBL; AF233330; AAF59928.1; JOINED; Genomic_DNA.
DR EMBL; AF233331; AAF59928.1; JOINED; Genomic_DNA.
DR EMBL; AL732590; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC003801; AAH03801.1; -; mRNA.
DR CCDS; CCDS15779.1; -. [P39429-1]
DR CCDS; CCDS71002.1; -. [P39429-2]
DR PIR; I61512; I61512.
DR RefSeq; NP_001277342.1; NM_001290413.1. [P39429-2]
DR RefSeq; NP_033448.2; NM_009422.3. [P39429-1]
DR AlphaFoldDB; P39429; -.
DR SMR; P39429; -.
DR BioGRID; 204303; 33.
DR CORUM; P39429; -.
DR DIP; DIP-468N; -.
DR IntAct; P39429; 49.
DR MINT; P39429; -.
DR STRING; 10090.ENSMUSP00000028311; -.
DR iPTMnet; P39429; -.
DR PhosphoSitePlus; P39429; -.
DR EPD; P39429; -.
DR MaxQB; P39429; -.
DR PaxDb; P39429; -.
DR PeptideAtlas; P39429; -.
DR PRIDE; P39429; -.
DR ProteomicsDB; 260736; -. [P39429-1]
DR ProteomicsDB; 260737; -. [P39429-2]
DR Antibodypedia; 2422; 766 antibodies from 49 providers.
DR DNASU; 22030; -.
DR Ensembl; ENSMUST00000028311; ENSMUSP00000028311; ENSMUSG00000026942. [P39429-1]
DR Ensembl; ENSMUST00000114234; ENSMUSP00000109872; ENSMUSG00000026942. [P39429-2]
DR GeneID; 22030; -.
DR KEGG; mmu:22030; -.
DR UCSC; uc008isl.2; mouse. [P39429-2]
DR UCSC; uc008ism.2; mouse. [P39429-1]
DR CTD; 7186; -.
DR MGI; MGI:101835; Traf2.
DR VEuPathDB; HostDB:ENSMUSG00000026942; -.
DR eggNOG; KOG0297; Eukaryota.
DR GeneTree; ENSGT00940000156621; -.
DR HOGENOM; CLU_021061_4_1_1; -.
DR InParanoid; P39429; -.
DR OMA; RHAEQEC; -.
DR PhylomeDB; P39429; -.
DR TreeFam; TF321154; -.
DR Reactome; R-MMU-3371378; Regulation by c-FLIP.
DR Reactome; R-MMU-5218900; CASP8 activity is inhibited.
DR Reactome; R-MMU-5357786; TNFR1-induced proapoptotic signaling.
DR Reactome; R-MMU-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-MMU-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-MMU-5668541; TNFR2 non-canonical NF-kB pathway.
DR Reactome; R-MMU-5675482; Regulation of necroptotic cell death.
DR Reactome; R-MMU-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway.
DR Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR Reactome; R-MMU-69416; Dimerization of procaspase-8.
DR Reactome; R-MMU-75893; TNF signaling.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 22030; 33 hits in 79 CRISPR screens.
DR ChiTaRS; Traf2; mouse.
DR PRO; PR:P39429; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; P39429; protein.
DR Bgee; ENSMUSG00000026942; Expressed in thymus and 206 other tissues.
DR ExpressionAtlas; P39429; baseline and differential.
DR Genevisible; P39429; MM.
DR GO; GO:0035631; C:CD40 receptor complex; IDA:BHF-UCL.
DR GO; GO:0005938; C:cell cortex; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:AgBase.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:1990604; C:IRE1-TRAF2-ASK1 complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:0045121; C:membrane raft; IDA:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0097057; C:TRAF2-GSTP1 complex; ISO:MGI.
DR GO; GO:0002947; C:tumor necrosis factor receptor superfamily complex; ISO:MGI.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISO:MGI.
DR GO; GO:0012506; C:vesicle membrane; IDA:MGI.
DR GO; GO:0005174; F:CD40 receptor binding; IPI:BHF-UCL.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; ISO:MGI.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0019903; F:protein phosphatase binding; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; ISO:MGI.
DR GO; GO:0046625; F:sphingolipid binding; ISS:UniProtKB.
DR GO; GO:0031996; F:thioesterase binding; ISO:MGI.
DR GO; GO:0043120; F:tumor necrosis factor binding; ISO:MGI.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; ISO:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; ISO:MGI.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0071732; P:cellular response to nitric oxide; IMP:MGI.
DR GO; GO:0097400; P:interleukin-17-mediated signaling pathway; IDA:MGI.
DR GO; GO:0048255; P:mRNA stabilization; IMP:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; NAS:UniProtKB.
DR GO; GO:0034351; P:negative regulation of glial cell apoptotic process; ISO:MGI.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:MGI.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IDA:AgBase.
DR GO; GO:1903721; P:positive regulation of I-kappaB phosphorylation; IDA:AgBase.
DR GO; GO:0032743; P:positive regulation of interleukin-2 production; ISO:MGI.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IBA:GO_Central.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:AgBase.
DR GO; GO:0002726; P:positive regulation of T cell cytokine production; ISO:MGI.
DR GO; GO:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:AgBase.
DR GO; GO:0097300; P:programmed necrotic cell death; IMP:MGI.
DR GO; GO:0051865; P:protein autoubiquitination; ISS:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; IMP:MGI.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0065003; P:protein-containing complex assembly; IDA:BHF-UCL.
DR GO; GO:0042981; P:regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0002637; P:regulation of immunoglobulin production; IMP:MGI.
DR GO; GO:0046328; P:regulation of JNK cascade; IDA:MGI.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; ISO:MGI.
DR GO; GO:0007165; P:signal transduction; IDA:MGI.
DR GO; GO:0023019; P:signal transduction involved in regulation of gene expression; IDA:MGI.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; ISS:UniProtKB.
DR CDD; cd03778; MATH_TRAF2; 1.
DR Gene3D; 2.60.210.10; -; 1.
DR Gene3D; 3.30.40.10; -; 3.
DR InterPro; IPR002083; MATH/TRAF_dom.
DR InterPro; IPR043211; TNF_rcpt-assoc_TRAF.
DR InterPro; IPR012227; TNF_rcpt-assoc_TRAF_met.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR027133; TRAF2.
DR InterPro; IPR037305; TRAF2_MATH.
DR InterPro; IPR032070; TRAF_BIRC3-bd.
DR InterPro; IPR018957; Znf_C3HC4_RING-type.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR InterPro; IPR001293; Znf_TRAF.
DR PANTHER; PTHR10131; PTHR10131; 1.
DR PANTHER; PTHR10131:SF21; PTHR10131:SF21; 1.
DR Pfam; PF16673; TRAF_BIRC3_bd; 1.
DR Pfam; PF00097; zf-C3HC4; 1.
DR Pfam; PF02176; zf-TRAF; 1.
DR PIRSF; PIRSF015614; TRAF; 1.
DR SMART; SM00061; MATH; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS50144; MATH; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
DR PROSITE; PS50145; ZF_TRAF; 2.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Apoptosis; Coiled coil; Cytoplasm;
KW Direct protein sequencing; Isopeptide bond; Lipid-binding; Metal-binding;
KW Phosphoprotein; Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q12933"
FT CHAIN 2..501
FT /note="TNF receptor-associated factor 2"
FT /id="PRO_0000056400"
FT DOMAIN 351..496
FT /note="MATH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00129"
FT ZN_FING 34..73
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 124..180
FT /note="TRAF-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT ZN_FING 177..233
FT /note="TRAF-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT REGION 283..293
FT /note="Important for interaction with BIRC2 and BIRC3"
FT COILED 298..348
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:Q12933"
FT MOD_RES 5
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12933"
FT MOD_RES 7
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q12933"
FT MOD_RES 11
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q12933"
FT MOD_RES 22
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q12933"
FT MOD_RES 117
FT /note="Phosphothreonine; by PKC"
FT /evidence="ECO:0000269|PubMed:19150425"
FT CROSSLNK 31
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q12933"
FT VAR_SEQ 62
FT /note="L -> LRCASILS (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9461607"
FT /id="VSP_007402"
FT MUTAGEN 34
FT /note="C->S: Loss of autoubiquitination."
FT /evidence="ECO:0000269|PubMed:11909853"
FT MUTAGEN 283
FT /note="E->A: Reduces interaction with BIRC2."
FT /evidence="ECO:0000269|PubMed:19815541"
FT MUTAGEN 292
FT /note="E->A: Almost abolishes interaction with BIRC2; when
FT associated with A-294."
FT /evidence="ECO:0000269|PubMed:19815541"
FT MUTAGEN 294
FT /note="E->A: Almost abolishes interaction with BIRC2; when
FT associated with A-292."
FT /evidence="ECO:0000269|PubMed:19815541"
SQ SEQUENCE 501 AA; 56026 MW; 043B391180365F10 CRC64;
MAAASVTSPG SLELLQPGFS KTLLGTRLEA KYLCSACKNI LRRPFQAQCG HRYCSFCLTS
ILSSGPQNCA ACVYEGLYEE GISILESSSA FPDNAARREV ESLPAVCPND GCTWKGTLKE
YESCHEGLCP FLLTECPACK GLVRLSEKEH HTEQECPKRS LSCQHCRAPC SHVDLEVHYE
VCPKFPLTCD GCGKKKIPRE TFQDHVRACS KCRVLCRFHT VGCSEMVETE NLQDHELQRL
REHLALLLSS FLEAQASPGT LNQVGPELLQ RCQILEQKIA TFENIVCVLN REVERVAVTA
EACSRQHRLD QDKIEALSNK VQQLERSIGL KDLAMADLEQ KVSELEVSTY DGVFIWKISD
FTRKRQEAVA GRTPAIFSPA FYTSRYGYKM CLRVYLNGDG TGRGTHLSLF FVVMKGPNDA
LLQWPFNQKV TLMLLDHNNR EHVIDAFRPD VTSSSFQRPV SDMNIASGCP LFCPVSKMEA
KNSYVRDDAI FIKAIVDLTG L
