Fig. 8. Oncogenic and energetic stress signals converge at the GSK3β–SIRT7 axis.

Short term and mild energetic stress activating AMPK to prime the phosphorylation of Thr263 leads SIRT7 to be further phosphorylated at Thr255/Ser259 by GSK3β, which prevents UBR5-mediated SIRT7 K48-polyubiquitination and subsequent proteasomal degradation. As a result, phosphorylated SIRT7 inhibits the integrity of the SCF-SKP2 E3 ligase complex which facilitates AKT K63 polyubiquitination and thus activation. In contrast, long term or extreme energetic stress and/or oncogenic signals hijack the GSK3β–SIRT7 axis by activating ERK2, leading to SIRT7 loss of phosphorylation, and AKT overactivation, which contributes to tumorigenesis, drug resistance, and cell survival. Thus, SIRT7 serves as a central hub that senses oncogenic signals and energetic stress and manipulates malignant progress.