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TRAF6
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<h2 id="function">Function</h2> <p>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 the signaling not only from the members of the TNF receptor superfamily, but also from the members of the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/TRANCE/RANKL and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including <a href="/facts/IRAK1/Lb6aVu78">IRAK1/IRAK</a>, <a href="/facts/Proto-oncogene_tyrosine-protein_kinase_Src/5SCJqCU4">SRC</a> 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 <a href="/facts/Ubiquitin/hpulmU3m">ubiquitin</a> conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. Two alternatively spliced transcript variants encoding identical proteins have been reported.<a class="footnote-ref" id="fnref:1" href="#fn:1"><sup>1</sup></a> </p> <h2 id="interactions">Interactions</h2> <p>TRAF6 has been shown to <a href="/facts/Protein-protein_interaction/etvm9Wmg">interact</a> with: </p> <ul><li><a href="/facts/ASK1/fAPmL4xH">ASK1</a>,<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a><a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a><a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a></li> <li><a href="/facts/CD40_(protein)/wnuXHEgD">CD40</a>,<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a><a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a></li> <li><a href="/facts/FHL2/jc80KwSJ">FHL2</a>,<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a></li> <li><a href="/facts/HSPB2/VH9QpkM1">HSPB2</a>,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a></li> <li><a href="/facts/IKBKG/JlWJabHI">IKBKG</a>,<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a></li> <li><a href="/facts/IRAK1/Lb6aVu78">IRAK1</a>,<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a></li> <li><a href="/facts/IRAK2/nYswHE00">IRAK2</a>,<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a></li> <li><a href="/facts/TAB1/oYfkqRKK">TAB1</a>,<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></li> <li><a href="/facts/MAP3K7IP2/lsoknLe4">MAP3K7IP2</a>,<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a></li> <li><a href="/facts/MAP3K7/Rg3Fxu0A">MAP3K7</a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a><a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a><a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a></li> <li><a href="/facts/PPP4C/PCkmu3Vn">PPP4C</a>,<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a></li> <li><a href="/facts/RANK/MSVmLtY2">RANK</a>,<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a><a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a><a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a><a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a></li> <li><a href="/facts/SDCBP/1FPY3ccc">SDCBP</a>,<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a></li> <li><a href="/facts/SIGIRR/cVX9c7CX">SIGIRR</a>,<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a></li> <li><a href="/facts/Sequestosome_1/oPFTII1M">Sequestosome 1</a>,<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a></li> <li><a href="/facts/TAX1BP1/ve7AuKP1">TAX1BP1</a>,<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a></li> <li><a href="/facts/TNFAIP3/8bSANn6c">TNFAIP3</a>,<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a><a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a></li> <li><a href="/facts/TNFRSF13B/ogcsJ8Yn">TNFRSF13B</a>,<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a></li> <li><a href="/facts/UBE2N/VKrFN5yK">UBE2N</a>,<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> and</li> <li><a href="/facts/Ubiquitin_C/jlyDw5JH">Ubiquitin C</a>.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a><a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a><a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a><a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a><a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Wajant H, Henkler F, Scheurich P (2001). "The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators". <i>Cell. Signal</i>. 13 (6): 389–400. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0898-6568%2801%2900160-7">10.1016/S0898-6568(01)00160-7</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11384837">11384837</a>.</li> <li>Vlantis K, Polykratis A, Welz PS, van Loo G, Pasparakis M, Wullaert A (2016). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893119">"TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice"</a>. <i>Gut</i>. 65 (6): 935–43. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1136%2Fgutjnl-2014-308323">10.1136/gutjnl-2014-308323</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893119">4893119</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/25761602">25761602</a>.</li> <li>Bradley JR, Pober JS (2001). <a href="https://doi.org/10.1038%2Fsj.onc.1204788">"Tumor necrosis factor receptor-associated factors (TRAFs)"</a>. <i>Oncogene</i>. 20 (44): 6482–91. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Fsj.onc.1204788">10.1038/sj.onc.1204788</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11607847">11607847</a>.</li> <li>Tanaka S, Nakamura K, Takahasi N, Suda T (2006). "Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system". <i>Immunol. Rev</i>. 208: 30–49. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1111%2Fj.0105-2896.2005.00327.x">10.1111/j.0105-2896.2005.00327.x</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16313339">16313339</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:13811917">13811917</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=TRAF6">TRAF6</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"Entrez Gene: TRAF6 TNF receptor-associated factor 6". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7189" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7189</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H (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. <a href="https://doi.org/10.1016%2Fs1097-2765%2800%2980283-x" target="_blank">https://doi.org/10.1016%2Fs1097-2765%2800%2980283-x</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>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. S2CID 12132452. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Mochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya-Tsuji J, Matsumoto K, Ichijo H (October 2000). "ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction". J. Biol. Chem. 275 (42): 32747–52. doi:10.1074/jbc.M003042200. PMID 10921914. <a href="https://doi.org/10.1074%2Fjbc.M003042200" target="_blank">https://doi.org/10.1074%2Fjbc.M003042200</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>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. Bibcode:1999PNAS...96.1234T. doi:10.1073/pnas.96.4.1234. PMC 15446. PMID 9990007. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15446" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC15446</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1170295" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1170295</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Bai S, Zha J, Zhao H, Ross FP, Teitelbaum SL (November 2008). "Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts". J. Biol. Chem. 283 (45): 30861–7. doi:10.1074/jbc.M802525200. PMC 2662164. PMID 18768464. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662164" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662164</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Wu Y, Liu J, Zhang Z, Huang H, Shen J, Zhang S, Jiang Y, Luo L, Yin Z (January 2009). "HSP27 regulates IL-1 stimulated IKK activation through interacting with TRAF6 and affecting its ubiquitination". Cell. Signal. 21 (1): 143–50. doi:10.1016/j.cellsig.2008.10.001. PMID 18950704. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Windheim M, Stafford M, Peggie M, Cohen P (March 2008). "Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase". Mol. Cell. Biol. 28 (5): 1783–91. doi:10.1128/MCB.02380-06. PMC 2258775. PMID 18180283. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258775" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258775</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Lamothe B, Campos AD, Webster WK, Gopinathan A, Hur L, Darnay BG (September 2008). "The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL". J. Biol. Chem. 283 (36): 24871–80. doi:10.1074/jbc.M802749200. PMC 2529010. PMID 18617513. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2529010" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2529010</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Chen F, Du Y, Zhang Z, Chen G, Zhang M, Shu HB, Zhai Z, Chen D (April 2008). "Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling". Cell. Signal. 20 (4): 666–74. doi:10.1016/j.cellsig.2007.12.002. PMID 18234474. S2CID 28812149. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (July 1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". J. Biol. Chem. 274 (27): 19403–10. doi:10.1074/jbc.274.27.19403. PMID 10383454. <a href="https://doi.org/10.1074%2Fjbc.274.27.19403" target="_blank">https://doi.org/10.1074%2Fjbc.274.27.19403</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Muzio M, Ni J, Feng P, Dixit VM (November 1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science. 278 (5343): 1612–5. Bibcode:1997Sci...278.1612M. doi:10.1126/science.278.5343.1612. PMID 9374458. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X (November 2001). "IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B". J. Biol. Chem. 276 (45): 41661–7. doi:10.1074/jbc.M102262200. PMID 11518704. <a href="https://doi.org/10.1074%2Fjbc.M102262200" target="_blank">https://doi.org/10.1074%2Fjbc.M102262200</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (October 1996). "TRAF6 is a signal transducer for interleukin-1". Nature. 383 (6599): 443–6. Bibcode:1996Natur.383..443C. doi:10.1038/383443a0. PMID 8837778. S2CID 4269027. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J (April 2003). "Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling". J. Biol. Chem. 278 (14): 12144–50. doi:10.1074/jbc.M300720200. PMID 12566447. <a href="https://doi.org/10.1074%2Fjbc.M300720200" target="_blank">https://doi.org/10.1074%2Fjbc.M300720200</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Li S, Strelow A, Fontana EJ, Wesche H (April 2002). "IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5567–72. Bibcode:2002PNAS...99.5567L. doi:10.1073/pnas.082100399. PMC 122810. PMID 11960013. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC122810" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC122810</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Ling L, Goeddel DV (August 2000). "T6BP, a TRAF6-interacting protein involved in IL-1 signaling". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9567–72. Bibcode:2000PNAS...97.9567L. doi:10.1073/pnas.170279097. PMC 16905. PMID 10920205. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC16905" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC16905</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Takaesu G, Ninomiya-Tsuji J, Kishida S, Li X, Stark GR, Matsumoto K (April 2001). "Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway". Mol. Cell. Biol. 21 (7): 2475–84. doi:10.1128/MCB.21.7.2475-2484.2001. PMC 86880. PMID 11259596. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC86880" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC86880</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (July 1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". J. Biol. Chem. 274 (27): 19403–10. doi:10.1074/jbc.274.27.19403. 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