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. 2019 Sep 5;20(18):4360. doi: 10.3390/ijms20184360

Figure 2.

Figure 2

Mechanism of TRA/GO action. (A) TRA/GO induces ROS production. ROS disrupts mitochondrial integrity, releasing SMAC/DIBLO into cytosol. Binding of SAMC to cIAPs prevent RIP1 ubiquitylation, allowing formation of death complex ripoptosome. (B) Binding of TRA/GO to HER2 causes HER2 homodimerization, eliciting HER2 signaling; this activates NF-kB through the canonic pathway, augmenting TNFα production. TNFα singling through TNFR1 promotes degradation of cIAPs. (C) HER2 signaling also activates MAPK pathway, resulting in activation RSK2 that phosphorylate caspase 8 at Thr263 site to induce caspase ubiquitination and proteosomal degradation. Degradation of caspase 8 leads to formation of necroptosome executing necroptosis. (D) ROS also contributes to MAPK activation.