Figure 1: HER2 suppresses apoptosis via multiple mechanisms in both extrinsic and intrinsic apoptotic pathways. HER2 expression is maintained and stabilized by Rab7 and Hsp90. HER2 activates PI3K-AKT signaling, which directly FOXO1/3a through phosphorylation. Suppression of FOXO proteins relieves their repression of survivin. AKT also inhibits p53, which prevents p53-mediated expression of the pro-apoptotic genes PUMA, NOXA, APAF1, and BAX. HER2 activates NF- κB in an AKT-dependent manner, which increases expression of survivin. In addition, HER2 increases XIAP levels, which inhibits TRAIL-induced apoptosis. Lastly, HER2 localization to the mitochondria suppresses apoptosis by inhibition of cytochrome c oxidase. Thus, HER2 initiates broad changes to cell signaling that results in cell survival and suppression of apoptosis in response to toxic therapies.