AKTs do not translocate to the nucleus upon stimulation but AKT3 can constitutively signal from the nuclear envelope

AKT is a central signaling protein kinase that plays a role in the regulation of cellular survival metabolism and cell growth, as well as in pathologies such as diabetes and cancer. Human AKT consists of three isoforms (AKT1-3) that may fulfill different functions. Here, we report that distinct subcellular localization of the iso-forms directly influences their activity and function. AKT1 is localized primarily in the cytoplasm, AKT2 in the nucleus, and AKT3 in the nucleus or nuclear envelope. None of the isoforms actively translocates into the nucleus upon stimulation. Interestingly, AKT3 at the nuclear envelope is constitutively phosphorylated, enabling a constant phosphorylation of TSC2 at this location. Knockdown of AKT3 induces moderate atten-uation of cell proliferation of breast cancer cells. We suggest that in addition to the stimulation-induced acti-vation of the lysosomal/cytoplasmic AKT1-TSC2 pathway, a subpopulation of TSC2 is constitutively inacti-vated by AKT3 at the nuclear envelope of transformed cells.

Automated summary

AKT is a central signaling protein kinase that plays a critical role in cellular survival metabolism and cell growth regulation, with its different isoforms having distinct subcellular localization and functions.