A1 Refereed original research article in a scientific journal
AXL-TBK1 driven AKT3 activation promotes metastasis
Authors: Arner, Emily N.; Alzhanova, Dina; Westcott, Jill M.; Hinz, Stefan; Tiron, Crina Elena; Blo, Magnus; Mai, Anja; Virtakoivu, Reetta; Phinney, Natalie; Nord, Silje; Aguilera, Kristina Y.; Rizvi, Ali; Toombs, Jason E.; Reese, Tanner C.; Fey, Vidal; Micklem, David; Gausdal, Gro; Ivaska, Johanna; Lorens, James B.; Brekken, Rolf A.
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Publishing place: WASHINGTON
Publication year: 2024
Journal: Science Signaling
Journal name in source: SCIENCE SIGNALING
Journal acronym: SCI SIGNAL
Article number: eado6057
Volume: 17
Issue: 867
Number of pages: 17
ISSN: 1945-0877
eISSN: 1937-9145
DOI: https://doi.org/10.1126/scisignal.ado6057
Web address : https://www.science.org/doi/10.1126/scisignal.ado6057
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.
Funding information in the publication:
National Institutes of Health: P30 CA142543
National Institutes of Health: R01 CA192381
National Institutes of Health: R01 CA243577
National Institutes of Health: U54 CA210181 P
NIH: NCI F99 CA253718
ACS: PF-21-184-01-CSM
CPRIT: CPRIT RP160157
Norwegian Research Council
Norwegian Cancer Society
Bergen Health Authority
