AXL-TBK1 driven AKT3 activation promotes metastasis

作者：Emily N. Arner, Dina Alzhanova, Jill M. Westcott, Stefan Hinz, Crina Tiron, Magnus Blø, Anja Mai, Reetta Virtakoivu, Natalie Z. Phinney, Silje Nord, Kristina Y. Aguilera, Ali A. Rizvi, Jason E. Toombs, Tanner C. Reese, Vidal Fey, David Micklem, Gro Gausdal, Johanna Ivaska, James B. Lorens, Rolf A. Brekken · 发表于：Science Signaling · 年份：2024 · DOI：10.1126/scisignal.ado6057 · 被引用次数：9 · 研究领域：Phagocytosis and Immune Regulation、Pancreatic and Hepatic Oncology Research、Neuroblastoma Research and Treatments

The receptor tyrosine kinase AXL promotes tumor progression, metastasis, and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we found that activation of AXL resulted in the phosphorylation of TANK-binding kinase 1 (TBK1) and the downstream activation of AKT3 and Snail, a transcription factor critical for EMT. Mechanistically, we showed that TBK1 directly bound to and phosphorylated AKT3 in a manner dependent on the multiprotein complex mTORC1. Upon activation, AKT3 interacted with and promoted the nuclear accumulation of Snail, which led to increased EMT as assessed by marker abundance. In human pancreatic ductal adenocarcinoma tissue, nuclear AKT3 colocalized with Snail and correlated with worse clinical outcomes. Primary mouse pancreatic cancer cells deficient in AKT3 showed reduced metastatic spread in vivo, suggesting selective AKT3 inhibition as a potential therapeutic avenue for targeting EMT in aggressive cancers.