Vimentin is a novel AKT1 target mediating motility and invasion

The PI3K/AKT signaling pathway is aberrant in a wide variety of cancers. Downstream effectors of AKT are involved in survival, growth, and metabolic-related pathways. In contrast, contradictory data relating to AKT effects on cell motility and invasion, crucial pro-metastatic processes, have been reported pointing to a potential cell type and isoform type-specific AKT driven function. By implication, study of AKT signaling should optimally be conducted in the appropriate intracellular environment. Prognosis in soft-tissue sarcoma (STS), aggressive malignancies of mesenchymal origin, is poor reflecting our modest abilities to control metastasis, an effort hampered by lack of insight into molecular mechanisms driving STS progression and dissemination. We examined the impact of the cancer progression relevant AKT pathway on the mesenchymal tumor cell internal milieu. We demonstrate that AKT1 activation induces STS cell motility and invasiveness at least partially via a novel interaction with the intermediate filament vimentin. The binding of AKT (tail region) to vimentin (head region) results in vimentin Ser39 phosphorylation enhancing the ability of vimentin to induce motility and invasion while protecting vimentin from caspase induced proteolysis. Moreover, vimentin phosphorylation was shown to enhance tumor and metastasis growth in vivo. Insights into this mesenchymal-related molecular mechanism may facilitate development of critically lacking therapeutic options for these devastating malignancies.