Abstract
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.
MeSH terms
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Animals
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Axl Receptor Tyrosine Kinase*
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Carcinoma, Pancreatic Ductal / genetics
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Carcinoma, Pancreatic Ductal / metabolism
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Carcinoma, Pancreatic Ductal / pathology
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Cell Line, Tumor
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Epithelial-Mesenchymal Transition*
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Humans
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Mechanistic Target of Rapamycin Complex 1 / genetics
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Mechanistic Target of Rapamycin Complex 1 / metabolism
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Mice
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Neoplasm Metastasis*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Phosphorylation
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Protein Serine-Threonine Kinases* / genetics
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Protein Serine-Threonine Kinases* / metabolism
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Proto-Oncogene Proteins c-akt* / genetics
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Proto-Oncogene Proteins c-akt* / metabolism
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Proto-Oncogene Proteins* / genetics
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Proto-Oncogene Proteins* / metabolism
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Receptor Protein-Tyrosine Kinases* / genetics
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Receptor Protein-Tyrosine Kinases* / metabolism
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Signal Transduction
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Snail Family Transcription Factors* / genetics
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Snail Family Transcription Factors* / metabolism
Substances
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Proto-Oncogene Proteins c-akt
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Axl Receptor Tyrosine Kinase
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins
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Snail Family Transcription Factors
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Receptor Protein-Tyrosine Kinases
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TBK1 protein, human
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Mechanistic Target of Rapamycin Complex 1