NUAK1 directly induces Akt signaling and substrate specificity, promoting cancer cell survival

Background: NUAK1 is a serine/threonine kinase member of the AMPKα-family, whose high expression associated with poor prognosis. However, regulation and functions in cancer remain poorly characterized. Here, we investigated NUAK1’s role signaling. Materials Methods: We performed bioinformatic analysis TCGA to study correlation between EGFR Akt phosphorylation several cancers. mainly studies on breast colon cell lines. Pharmacological or shRNA-dependent inhibition demonstrated its insulin-dependent In vitro assays were demonstrate direct by NUAK1, proximity ligation association cells. Cell fractionation immunofluorescence analyzed subcellular localization, qPCR Akt/ FOXO1/3a axis. used 2D 3D cultures for survival monitored death using commercial kits. Results: Based public data, reported that correlates at Ser-473 Using pharmacological silencing, found activates signaling, regulating GSK3β but not TSC2 phosphorylation. Mechanistically, interacts directly phosphorylates it Ser-473. Comparing mTOR revealed an Akt-dynamic activation -substrate specificity depending mTORC2. The Akt-substrate could be co-localization early endosomes. Functionally, NUAK1/Akt/FOXO1/3a axis reduced p21CIP1 p27KIP1 induced FoxM1 expression. Additionally, our identified promotes growth factor-dependent manner, potentiates effect MK-2206, inhibitor. Conclusion: contrast other AMPK-related members, regulates signaling via Thus, targeting either alone combined inhibitors, may effective cancers hyperactivated Funding: ANID/Fondecyt 1191172 1201215 No conflict interest.