Biology:TRAF2

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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:

Model organisms

Model organisms have been used in the study of TRAF2 function. A conditional knockout mouse line called Traf2tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[61] Male and female animals underwent a standardized phenotypic screen[62] to determine the effects of deletion.[63][64][65][66] Additional screens performed: - In-depth immunological phenotyping[67]

References

  1. ↑ 1.0 1.1 "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. September 1995. doi:10.1042/bj3090825. PMID 7639698. 
  2. ↑ "Entrez Gene: TRAF2 TNF receptor-associated factor 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7186. 
  3. ↑ "ASK1 is essential for JNK/SAPK activation by TRAF2". Mol. Cell 2 (3): 389–95. September 1998. doi:10.1016/s1097-2765(00)80283-x. PMID 9774977. 
  4. ↑ "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)". Oncogene 18 (42): 5814–20. October 1999. doi:10.1038/sj.onc.1202975. PMID 10523862. 
  5. ↑ "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. October 2006. doi:10.1083/jcb.200604129. PMID 17015619. 
  6. ↑ 6.0 6.1 6.2 "Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALT lymphoma-associated protein". J. Biol. Chem. 275 (15): 11114–20. April 2000. doi:10.1074/jbc.275.15.11114. PMID 10753917. 
  7. ↑ 7.0 7.1 "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. November 1996. doi:10.1073/pnas.93.24.13973. PMID 8943045. Bibcode: 1996PNAS...9313973S. 
  8. ↑ 8.0 8.1 "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. May 1996. doi:10.1073/pnas.93.10.4974. PMID 8643514. Bibcode: 1996PNAS...93.4974U. 
  9. ↑ 9.0 9.1 "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914–25. Dec 1997. doi:10.1093/emboj/16.23.6914. PMID 9384571. 
  10. ↑ 10.0 10.1 "TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2". Nature 416 (6878): 345–7. March 2002. doi:10.1038/416345a. PMID 11907583. Bibcode: 2002Natur.416..345L. https://zenodo.org/record/1233217. 
  11. ↑ "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. October 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
  12. ↑ "FLASH coordinates NF-kappa B activity via TRAF2". J. Biol. Chem. 276 (27): 25073–7. July 2001. doi:10.1074/jbc.M102941200. PMID 11340079. 
  13. ↑ 13.0 13.1 "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. January 1998. doi:10.1128/MCB.18.1.558. PMID 9418902. 
  14. ↑ "Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B". Biochem. Biophys. Res. Commun. 242 (3): 613–20. January 1998. doi:10.1006/bbrc.1997.8016. PMID 9464265. 
  15. ↑ "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. November 1998. PMID 9794406. 
  16. ↑ "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. May 1998. doi:10.1074/jbc.273.21.13353. PMID 9582383. 
  17. ↑ "Crystallographic analysis of CD40 recognition and signaling by human TRAF2". Proc. Natl. Acad. Sci. U.S.A. 96 (15): 8408–13. July 1999. doi:10.1073/pnas.96.15.8408. PMID 10411888. Bibcode: 1999PNAS...96.8408M. 
  18. ↑ "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. February 1999. doi:10.1073/pnas.96.4.1234. PMID 9990007. Bibcode: 1999PNAS...96.1234T. 
  19. ↑ 19.0 19.1 19.2 19.3 "MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1". Nature 385 (6616): 540–4. February 1997. doi:10.1038/385540a0. PMID 9020361. 
  20. ↑ "Casper is a FADD- and caspase-related inducer of apoptosis". Immunity 6 (6): 751–63. June 1997. doi:10.1016/S1074-7613(00)80450-1. PMID 9208847. 
  21. ↑ "The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways". Curr. Biol. 10 (11): 640–8. June 2000. doi:10.1016/s0960-9822(00)00512-1. PMID 10837247. 
  22. ↑ 22.0 22.1 "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. June 2001. doi:10.1128/MCB.21.12.3986-3994.2001. PMID 11359906. 
  23. ↑ 23.0 23.1 23.2 "PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination". Mol. Cell 33 (1): 30–42. January 2009. doi:10.1016/j.molcel.2008.11.023. PMID 19150425. 
  24. ↑ "Identification and characterization of an IkappaB kinase". Cell 90 (2): 373–83. July 1997. doi:10.1016/S0092-8674(00)80344-X. PMID 9244310. 
  25. ↑ "Caveolin-1 associates with TRAF2 to form a complex that is recruited to tumor necrosis factor receptors". J. Biol. Chem. 276 (11): 8341–9. March 2001. doi:10.1074/jbc.M007116200. PMID 11112773. 
  26. ↑ "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. March 2002. doi:10.1074/jbc.C100661200. PMID 11805080. 
  27. ↑ "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. March 2002. doi:10.1016/s0960-9822(02)00687-5. PMID 11882293. 
  28. ↑ "A mammalian homolog of Drosophila schnurri, KRC, regulates TNF receptor-driven responses and interacts with TRAF2". Mol. Cell 9 (1): 121–31. January 2002. doi:10.1016/s1097-2765(01)00434-8. PMID 11804591. 
  29. ↑ "TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction". J. Biol. Chem. 274 (42): 30202–8. October 1999. doi:10.1074/jbc.274.42.30202. PMID 10514511. 
  30. ↑ "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. May 2001. doi:10.1074/jbc.C100103200. PMID 11278268. 
  31. ↑ "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 & Development 13 (10): 1297–308. May 1999. doi:10.1101/gad.13.10.1297. PMID 10346818. 
  32. ↑ "Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production". Nature Immunology 8 (1): 57–63. January 2007. doi:10.1038/ni1421. PMID 17143273. 
  33. ↑ "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. April 2000. doi:10.1016/s1097-2765(00)80244-0. PMID 10882101. 
  34. ↑ "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. August 1998. doi:10.1074/jbc.273.35.22681. PMID 9712898. 
  35. ↑ "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. September 1999. PMID 10477597. 
  36. ↑ "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. August 1998. doi:10.1074/jbc.273.32.20551. PMID 9685412. 
  37. ↑ "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. March 1999. doi:10.1074/jbc.274.12.7724. PMID 10075662. 
  38. ↑ "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. Dec 1998. doi:10.1074/jbc.273.51.34120. PMID 9852070. 
  39. ↑ "Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase". FEBS Lett. 443 (3): 297–302. January 1999. doi:10.1016/S0014-5793(98)01731-1. PMID 10025951. 
  40. ↑ 40.0 40.1 40.2 40.3 "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. August 1996. doi:10.1074/jbc.271.33.19935. PMID 8702708. 
  41. ↑ 41.0 41.1 "TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex". Immunity 4 (4): 387–96. April 1996. doi:10.1016/S1074-7613(00)80252-6. PMID 8612133. 
  42. ↑ 42.0 42.1 "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. September 2001. doi:10.1074/jbc.M104837200. PMID 11479302. 
  43. ↑ "Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling". J. Biol. Chem. 277 (10): 7996–8003. March 2002. doi:10.1074/jbc.M111423200. PMID 11777919. 
  44. ↑ 44.0 44.1 44.2 44.3 44.4 "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. 6 (2): 97–105. February 2004. doi:10.1038/ncb1086. PMID 14743216. 
  45. ↑ 45.0 45.1 "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. August 1996. doi:10.1073/pnas.93.16.8241. PMID 8710854. Bibcode: 1996PNAS...93.8241R. 
  46. ↑ "NF-kappaB activation through IKK-i-dependent I-TRAF/TANK phosphorylation". Genes Cells 5 (3): 191–202. March 2000. doi:10.1046/j.1365-2443.2000.00315.x. PMID 10759890. 
  47. ↑ "NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase". EMBO J. 18 (23): 6694–704. Dec 1999. doi:10.1093/emboj/18.23.6694. PMID 10581243. 
  48. ↑ "Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription". EMBO J. 19 (18): 4976–85. September 2000. doi:10.1093/emboj/19.18.4976. PMID 10990461. 
  49. ↑ "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. June 1996. doi:10.1073/pnas.93.13.6721. PMID 8692885. Bibcode: 1996PNAS...93.6721S. 
  50. ↑ "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. July 2000. doi:10.1084/jem.192.1.137. PMID 10880535. 
  51. ↑ 51.0 51.1 "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. May 1997. doi:10.1074/jbc.272.22.14029. PMID 9162022. 
  52. ↑ "ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5". J. Biol. Chem. 272 (21): 13471–4. May 1997. doi:10.1074/jbc.272.21.13471. PMID 9153189. 
  53. ↑ 53.0 53.1 "TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways". Cell 84 (2): 299–308. January 1996. doi:10.1016/S0092-8674(00)80984-8. PMID 8565075. 
  54. ↑ "Role of TNF receptor-associated factor 2 in the activation of IgM secretion by CD40 and CD120b". J. Immunol. 168 (7): 3318–22. April 2002. doi:10.4049/jimmunol.168.7.3318. PMID 11907088. 
  55. ↑ "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. October 2008. doi:10.1016/j.bbrc.2008.07.103. PMID 18671942. 
  56. ↑ "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. April 2003. doi:10.1074/jbc.M208672200. PMID 12571250. 
  57. ↑ "A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction". Cell 101 (7): 777–87. June 2000. doi:10.1016/S0092-8674(00)80889-2. PMID 10892748. 
  58. ↑ "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. June 2000. doi:10.1016/S1097-2765(00)80270-1. PMID 10911999. 
  59. ↑ "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. April 1997. doi:10.1084/jem.185.7.1275. PMID 9104814. 
  60. ↑ "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. October 2000. doi:10.1016/S0092-8674(00)00126-4. PMID 11057907. 
  61. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. 
  62. ↑ 62.0 62.1 "International Mouse Phenotyping Consortium". http://www.mousephenotype.org/data/search?q=Traf2#fq=*:*&facet=gene. 
  63. ↑ "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. Jun 2011. doi:10.1038/nature10163. PMID 21677750. 
  64. ↑ "Mouse library set to be knockout". Nature 474 (7351): 262–3. Jun 2011. doi:10.1038/474262a. PMID 21677718. 
  65. ↑ "A mouse for all reasons". Cell 128 (1): 9–13. Jan 2007. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  66. ↑ "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. 2013. doi:10.1016/j.cell.2013.06.022. PMID 23870131. 
  67. ↑ 67.0 67.1 "Infection and Immunity Immunophenotyping (3i) Consortium". http://www.immunophenotyping.org/data/search?keys=Traf2&field_gene_construct_tid=All. 

Further reading




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