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. Author manuscript; available in PMC: 2014 Jan 1.
Published in final edited form as: Cell Signal. 2012 Sep 7;25(1):247–254. doi: 10.1016/j.cellsig.2012.09.003

Figure 6. Working model.

Figure 6

Dox-induced double-stranded breaks (DSBs) activate PARP-1 and ATM. PARP-1 signalosome formation promotes NEMO SUMOylation. The coupled export of ATM and sumoylated NEMO translocates to the cytoplasm and assembles a large complex containing TRAF6, cIAP, ELKS. Lys63-linked polyubiquitination of TRAF6 or ELKS recruits TAB2/TAK1 complex and TRAF6 further promotes Lys63-linked polyubiquitination of TAK1 at Lys-158 site. TAK1 with Lys63-linked polyubiquitination recruits IKKs complex and activates IKKs and NF-κB. After TAK1 activation, USP4 deubiquitinates TAK1 with Lys63-linked polyubiquitination and inhibits TAK1-mediated downstream signal transduction. Meanwhile, E3 ligase ITCH catalyzes Lys48-linked polyubiquitination of TAK1 and promotes TAK1 degradation to terminate downstream signal transduction.