RT Journal Article SR Electronic T1 TRAF2: A Double-Edged Sword? JF Science's STKE JO Sci. STKE FD American Association for the Advancement of Science SP pe7 OP pe7 DO 10.1126/stke.2722005pe7 VO 2005 IS 272 A1 Xia, Zong-Ping A1 Chen, Zhijian J. YR 2005 UL http://stke.sciencemag.org/content/2005/272/pe7.abstract AB Ubiquitination is best known for its role in targeting proteins for degradation by the proteasome, but evidence of the nonproteolytic functions of ubiquitin is also rapidly accumulating. One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor–associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K63)–linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism. Some TRAF proteins, such as TRAF2 and TRAF3, have recently been shown to have a positive role in the canonical pathway that activates nuclear factor κB (NF-κB) through IκB kinase β (IKKβ), but a negative role in the noncanonical pathway that activates NF-κB through IKKα. These opposing roles of TRAF proteins may be linked to their ability to synthesize distinct forms of polyubiquitin chains. Indeed, the TRAF2-interacting protein RIP can mediate IKK activation when it is modified by K63 polyubiquitin chains, but is targeted to degradation by the proteasome when it is K48-polyubiquitinted by the NF-κB inhibitor A20. Thus, ubiquitin chains are dynamic switches that can influence signaling outputs in dramatically different ways.