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AXL-TBK1 driven AKT3 activation promotes metastasis

GSE274874 Homo sapiens Expression profiling by high throughput sequencing 5 samples Submitted 2024/12/17 Platform GPL18573
Summary
The receptor tyrosine kinase AXL promotes tumor progression, metastasis and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we report that activation of AXL results in TANK-binding kinase 1 (TBK1) phosphorylation, subsequent TBK1-dependent phosphorylation of AKT3 (pAKT3) and nuclear accumulation of pAKT3 and the EMT transcription factor (EMT-TF) Snail. Mechanistically, we show that (i) TBK1 directly binds and phosphorylates AKT3, in an mTORC1 dependent manner. Once activated, AKT3 interacts with Snail and promotes the accumulation of nuclear Snail to drive EMT. Congruently, in human pancreatic ductaladenocarcinoma tissue, nuclear AKT3 co-localizes with Snail and correlates with worse clinical outcome. AKT3 knockout in tumor cells significantly reduced metastatic spread in mice suggesting that selective AKT3 inhibition represents a novel therapeutic avenue for targeting EMT in aggressive cancers.
Published in
AXL-TBK1 driven AKT3 activation promotes metastasis
Arner EN, Alzhanova D, Westcott JM et al. · Science signaling 2024 · PMID 39689180 · doi:10.1126/scisignal.ado6057
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Also filed as BioProject PRJNA1148385 and SRA study SRP526544. Searching any of these in the dataset finder brings you back here.

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