TRAF2

TNF receptor-associated factor 2

PDB rendering based on 1ca4.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsTRAF2 ; MGC:45012; TRAP; TRAP3
External IDsOMIM: 601895 MGI: 101835 HomoloGene: 22520 GeneCards: TRAF2 Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez718622030
EnsemblENSG00000127191ENSMUSG00000026942
UniProtQ12933P39429
RefSeq (mRNA)NM_021138NM_001290413
RefSeq (protein)NP_066961NP_001277342
Location (UCSC)Chr 9:
139.78 – 139.82 Mb		Chr 2:
25.52 – 25.55 Mb
PubMed search

TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.[1]

Function

The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from members of the TNF receptor superfamily. This protein directly interacts with TNF receptors, and forms complexes with other TRAF proteins. TRAF2 is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-κB. The protein complex formed by TRAF2 and TRAF1 interacts with the IAP family members cIAP1 and cIAP2, and functions as a mediator of the anti-apoptotic signals from TNF receptors. The interaction of this protein with TRADD, a TNF receptor associated apoptotic signal transducer, ensures the recruitment of IAPs for the direct inhibition of caspase activation. cIAP1 can ubiquitinate and induce the degradation of this protein, and thus potentiate TNF-induced apoptosis. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of only one transcript has been determined.[2]

Signaling pathway of TNF-R1. Dashed grey lines represent multiple steps

Interactions

TRAF2 has been shown to interact with:


References

  1. ↑ 1.0 1.1 Song HY, Donner DB (September 1995). "Association of a RING finger protein with the cytoplasmic domain of the human type-2 tumour necrosis factor receptor". Biochem J 309 (Pt 3): 825–9. PMC 1135706. PMID 7639698.
  2. ↑ "Entrez Gene: TRAF2 TNF receptor-associated factor 2".
  3. ↑ Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M et al. (September 1998). "ASK1 is essential for JNK/SAPK activation by TRAF2". Mol. Cell 2 (3): 389–95. doi:10.1016/s1097-2765(00)80283-x. PMID 9774977.
  4. ↑ Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR (October 1999). "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)". Oncogene 18 (42): 5814–20. doi:10.1038/sj.onc.1202975. PMID 10523862.
  5. ↑ Gan B, Peng X, Nagy T, Alcaraz A, Gu H, Guan JL (October 2006). "Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways". J. Cell Biol. 175 (1): 121–33. doi:10.1083/jcb.200604129. PMC 2064504. PMID 17015619.
  6. ↑ 6.0 6.1 6.2 Yoneda T, Imaizumi K, Maeda M, Yui D, Manabe T, Katayama T et al. (April 2000). "Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALT lymphoma-associated protein". J. Biol. Chem. 275 (15): 11114–20. doi:10.1074/jbc.275.15.11114. PMID 10753917.
  7. ↑ 7.0 7.1 Shu HB, Takeuchi M, Goeddel DV (November 1996). "The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex". Proc. Natl. Acad. Sci. U.S.A. 93 (24): 13973–8. doi:10.1073/pnas.93.24.13973. PMC 19479. PMID 8943045.
  8. ↑ 8.0 8.1 Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL (May 1996). "Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors". Proc. Natl. Acad. Sci. U.S.A. 93 (10): 4974–8. doi:10.1073/pnas.93.10.4974. PMC 39390. PMID 8643514.
  9. ↑ 9.0 9.1 Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (Dec 1997). "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914–25. doi:10.1093/emboj/16.23.6914. PMC 1170295. PMID 9384571.
  10. ↑ 10.0 10.1 Li X, Yang Y, Ashwell JD (March 2002). "TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2". Nature 416 (6878): 345–7. doi:10.1038/416345a. PMID 11907583.
  11. ↑ Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
  12. ↑ Choi YH, Kim KB, Kim HH, Hong GS, Kwon YK, Chung CW et al. (July 2001). "FLASH coordinates NF-kappa B activity via TRAF2". J. Biol. Chem. 276 (27): 25073–7. doi:10.1074/jbc.M102941200. PMID 11340079.
  13. ↑ 13.0 13.1 Arch RH, Thompson CB (January 1998). "4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB". Mol. Cell. Biol. 18 (1): 558–65. PMC 121523. PMID 9418902.
  14. ↑ Jang IK, Lee ZH, Kim YJ, Kim SH, Kwon BS (January 1998). "Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B". Biochem. Biophys. Res. Commun. 242 (3): 613–20. doi:10.1006/bbrc.1997.8016. PMID 9464265.
  15. ↑ Yamamoto H, Kishimoto T, Minamoto S (November 1998). "NF-kappaB activation in CD27 signaling: involvement of TNF receptor-associated factors in its signaling and identification of functional region of CD27". J. Immunol. 161 (9): 4753–9. PMID 9794406.
  16. ↑ Akiba H, Nakano H, Nishinaka S, Shindo M, Kobata T, Atsuta M et al. (May 1998). "CD27, a member of the tumor necrosis factor receptor superfamily, activates NF-kappaB and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kappaB-inducing kinase". J. Biol. Chem. 273 (21): 13353–8. doi:10.1074/jbc.273.21.13353. PMID 9582383.
  17. ↑ McWhirter SM, Pullen SS, Holton JM, Crute JJ, Kehry MR, Alber T (July 1999). "Crystallographic analysis of CD40 recognition and signaling by human TRAF2". Proc. Natl. Acad. Sci. U.S.A. 96 (15): 8408–13. doi:10.1073/pnas.96.15.8408. PMC 17529. PMID 10411888.
  18. ↑ Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J (February 1999). "Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40". Proc. Natl. Acad. Sci. U.S.A. 96 (4): 1234–9. doi:10.1073/pnas.96.4.1234. PMC 15446. PMID 9990007.
  19. ↑ 19.0 19.1 19.2 19.3 Malinin NL, Boldin MP, Kovalenko AV, Wallach D (February 1997). "MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1". Nature 385 (6616): 540–4. doi:10.1038/385540a0. PMID 9020361.
  20. ↑ Shu HB, Halpin DR, Goeddel DV (June 1997). "Casper is a FADD- and caspase-related inducer of apoptosis". Immunity 6 (6): 751–63. doi:10.1016/S1074-7613(00)80450-1. PMID 9208847.
  21. ↑ Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M et al. (June 2000). "The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways". Curr. Biol. 10 (11): 640–8. doi:10.1016/s0960-9822(00)00512-1. PMID 10837247.
  22. ↑ 22.0 22.1 Devin A, Lin Y, Yamaoka S, Li Z, Karin M (June 2001). "The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF". Mol. Cell. Biol. 21 (12): 3986–94. doi:10.1128/MCB.21.12.3986-3994.2001. PMC 87061. PMID 11359906.
  23. ↑ 23.0 23.1 23.2 Li S, Wang L, Dorf ME (January 2009). "PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination". Mol. Cell 33 (1): 30–42. doi:10.1016/j.molcel.2008.11.023. PMC 2643372. PMID 19150425.
  24. ↑ Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M (July 1997). "Identification and characterization of an IkappaB kinase". Cell 90 (2): 373–83. doi:10.1016/S0092-8674(00)80344-X. PMID 9244310.
  25. ↑ Feng X, Gaeta ML, Madge LA, Yang JH, Bradley JR, Pober JS (March 2001). "Caveolin-1 associates with TRAF2 to form a complex that is recruited to tumor necrosis factor receptors". J. Biol. Chem. 276 (11): 8341–9. doi:10.1074/jbc.M007116200. PMID 11112773.
  26. ↑ Cao H, Courchesne WE, Mastick CC (March 2002). "A phosphotyrosine-dependent protein interaction screen reveals a role for phosphorylation of caveolin-1 on tyrosine 14: recruitment of C-terminal Src kinase". J. Biol. Chem. 277 (11): 8771–4. doi:10.1074/jbc.C100661200. PMID 11805080.
  27. ↑ Yan M, Zhang Z, Brady JR, Schilbach S, Fairbrother WJ, Dixit VM (March 2002). "Identification of a novel death domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice". Curr. Biol. 12 (5): 409–13. doi:10.1016/s0960-9822(02)00687-5. PMID 11882293.
  28. ↑ Oukka M, Kim ST, Lugo G, Sun J, Wu LC, Glimcher LH (January 2002). "A mammalian homolog of Drosophila schnurri, KRC, regulates TNF receptor-driven responses and interacts with TRAF2". Mol. Cell 9 (1): 121–31. doi:10.1016/s1097-2765(01)00434-8. PMID 11804591.
  29. ↑ Ye X, Mehlen P, Rabizadeh S, VanArsdale T, Zhang H, Shin H et al. (October 1999). "TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction". J. Biol. Chem. 274 (42): 30202–8. doi:10.1074/jbc.274.42.30202. PMID 10514511.
  30. ↑ Luftig MA, Cahir-McFarland E, Mosialos G, Kieff E (May 2001). "Effects of the NIK aly mutation on NF-kappaB activation by the Epstein-Barr virus latent infection membrane protein, lymphotoxin beta receptor, and CD40". J. Biol. Chem. 276 (18): 14602–6. doi:10.1074/jbc.C100103200. PMID 11278268.
  31. ↑ Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (May 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 (10): 1297–308. doi:10.1101/gad.13.10.1297. PMC 316725. PMID 10346818.
  32. ↑ Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K et al. (April 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 (4): 649–58. doi:10.1016/s1097-2765(00)80244-0. PMID 10882101.
  33. ↑ Yuasa T, Ohno S, Kehrl JH, Kyriakis JM (August 1998). "Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38". J. Biol. Chem. 273 (35): 22681–92. doi:10.1074/jbc.273.35.22681. PMID 9712898.
  34. ↑ Shi CS, Leonardi A, Kyriakis J, Siebenlist U, Kehrl JH (September 1999). "TNF-mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related". J. Immunol. 163 (6): 3279–85. PMID 10477597.
  35. ↑ Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB (August 1998). "Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase". J. Biol. Chem. 273 (32): 20551–5. doi:10.1074/jbc.273.32.20551. PMID 9685412.
  36. ↑ Darnay BG, Ni J, Moore PA, Aggarwal BB (March 1999). "Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif". J. Biol. Chem. 274 (12): 7724–31. doi:10.1074/jbc.274.12.7724. PMID 10075662.
  37. ↑ Galibert L, Tometsko ME, Anderson DM, Cosman D, Dougall WC (Dec 1998). "The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily". J. Biol. Chem. 273 (51): 34120–7. doi:10.1074/jbc.273.51.34120. PMID 9852070.
  38. ↑ Kim HH, Lee DE, Shin JN, Lee YS, Jeon YM, Chung CH et al. (January 1999). "Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase". FEBS Lett. 443 (3): 297–302. doi:10.1016/S0014-5793(98)01731-1. PMID 10025951.
  39. ↑ 39.0 39.1 39.2 39.3 Takeuchi M, Rothe M, Goeddel DV (August 1996). "Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins". J. Biol. Chem. 271 (33): 19935–42. doi:10.1074/jbc.271.33.19935. PMID 8702708.
  40. ↑ 40.0 40.1 Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV (April 1996). "TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex". Immunity 4 (4): 387–96. doi:10.1016/S1074-7613(00)80252-6. PMID 8612133.
  41. ↑ 41.0 41.1 Tada K, Okazaki T, Sakon S, Kobarai T, Kurosawa K, Yamaoka S et al. (September 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 (39): 36530–4. doi:10.1074/jbc.M104837200. PMID 11479302.
  42. ↑ Xia P, Wang L, Moretti PA, Albanese N, Chai F, Pitson SM et al. (March 2002). "Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling". J. Biol. Chem. 277 (10): 7996–8003. doi:10.1074/jbc.M111423200. PMID 11777919.
  43. ↑ 43.0 43.1 43.2 43.3 43.4 Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K et al. (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216.
  44. ↑ 44.0 44.1 Rothe M, Xiong J, Shu HB, Williamson K, Goddard A, Goeddel DV (August 1996). "I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction". Proc. Natl. Acad. Sci. U.S.A. 93 (16): 8241–6. doi:10.1073/pnas.93.16.8241. PMC 38654. PMID 8710854.
  45. ↑ Nomura F, Kawai T, Nakanishi K, Akira S (March 2000). "NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation". Genes Cells 5 (3): 191–202. doi:10.1046/j.1365-2443.2000.00315.x. PMID 10759890.
  46. ↑ Pomerantz JL, Baltimore D (Dec 1999). "NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase". EMBO J. 18 (23): 6694–704. doi:10.1093/emboj/18.23.6694. PMC 1171732. PMID 10581243.
  47. ↑ Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M et al. (September 2000). "Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription". EMBO J. 19 (18): 4976–85. doi:10.1093/emboj/19.18.4976. PMC 314216. PMID 10990461.
  48. ↑ Song HY, Rothe M, Goeddel DV (June 1996). "The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation". Proc. Natl. Acad. Sci. U.S.A. 93 (13): 6721–5. doi:10.1073/pnas.93.13.6721. PMC 39093. PMID 8692885.
  49. ↑ Xia XZ, Treanor J, Senaldi G, Khare SD, Boone T, Kelley M et al. (July 2000). "TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation". J. Exp. Med. 192 (1): 137–43. doi:10.1084/jem.192.1.137. PMC 1887716. PMID 10880535.
  50. ↑ 50.0 50.1 Marsters SA, Ayres TM, Skubatch M, Gray CL, Rothe M, Ashkenazi A (May 1997). "Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-kappaB and AP-1". J. Biol. Chem. 272 (22): 14029–32. doi:10.1074/jbc.272.22.14029. PMID 9162022.
  51. ↑ Hsu H, Solovyev I, Colombero A, Elliott R, Kelley M, Boyle WJ (May 1997). "ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5". J. Biol. Chem. 272 (21): 13471–4. doi:10.1074/jbc.272.21.13471. PMID 9153189.
  52. ↑ 52.0 52.1 Hsu H, Shu HB, Pan MG, Goeddel DV (January 1996). "TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways". Cell 84 (2): 299–308. doi:10.1016/S0092-8674(00)80984-8. PMID 8565075.
  53. ↑ Hostager BS, Bishop GA (April 2002). "Role of TNF receptor-associated factor 2 in the activation of IgM secretion by CD40 and CD120b". J. Immunol. 168 (7): 3318–22. doi:10.4049/jimmunol.168.7.3318. PMID 11907088.
  54. ↑ Carpentier I, Coornaert B, Beyaert R (October 2008). "Smurf2 is a TRAF2 binding protein that triggers TNF-R2 ubiquitination and TNF-R2-induced JNK activation". Biochem. Biophys. Res. Commun. 374 (4): 752–7. doi:10.1016/j.bbrc.2008.07.103. PMID 18671942.
  55. ↑ Kuai J, Nickbarg E, Wooters J, Qiu Y, Wang J, Lin LL (April 2003). "Endogenous association of TRAF2, TRAF3, cIAP1, and Smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis". J. Biol. Chem. 278 (16): 14363–9. doi:10.1074/jbc.M208672200. PMID 12571250.
  56. ↑ Park YC, Ye H, Hsia C, Segal D, Rich RL, Liou HC et al. (June 2000). "A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction". Cell 101 (7): 777–87. doi:10.1016/S0092-8674(00)80889-2. PMID 10892748.
  57. ↑ Tsao DH, McDonagh T, Telliez JB, Hsu S, Malakian K, Xu GY et al. (June 2000). "Solution structure of N-TRADD and characterization of the interaction of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway". Mol. Cell 5 (6): 1051–7. doi:10.1016/S1097-2765(00)80270-1. PMID 10911999.
  58. ↑ Lee SY, Lee SY, Choi Y (April 1997). "TRAF-interacting protein (TRIP): a novel component of the tumor necrosis factor receptor (TNFR)- and CD30-TRAF signaling complexes that inhibits TRAF2-mediated NF-kappaB activation". J. Exp. Med. 185 (7): 1275–85. doi:10.1084/jem.185.7.1275. PMC 2196258. PMID 9104814.
  59. ↑ Deng L, Wang C, Spencer E, Yang L, Braun A, You J et al. (October 2000). "Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain". Cell 103 (2): 351–61. doi:10.1016/S0092-8674(00)00126-4. PMID 11057907.

Further reading

  • Wajant H, Henkler F, Scheurich P (2001). "The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators". Cell. Signal. 13 (6): 389–400. doi:10.1016/S0898-6568(01)00160-7. PMID 11384837.
  • Bradley JR, Pober JS (2001). "Tumor necrosis factor receptor-associated factors (TRAFs)". Oncogene 20 (44): 6482–91. doi:10.1038/sj.onc.1204788. PMID 11607847.