Novel roles of the adaptor associated kinase 1 (AAK1)

Abstract

Epithelial-mesenchymal transition (EMT) is a reversible cellular program that is involved in normal biological processes, such as embryogenesis and wound healing, and pathological processes, such as fibrosis and cancer. In cancer, EMT can drive therapeutic resistance and metastasis, the hallmarks of malignancy. We recently developed a mass spectrometry-based proteomics approach to study protein complexes in native cells and tissues. Using this tool, we characterized protein complexes that are differentially enriched between epithelial-like and mesenchymal-like states in hepatocellular carcinoma (HCC). We found that the adaptor associated kinase 1 (AAK1) protein complex is highly enriched in mesenchymal-like HCC cells and tissues, and that the depletion of AAK1 resulted in EMT reversal. Before this, AAK1 was mostly known for its role in the regulation of Clathrin-mediated endocytosis through the phosphorylation of adaptor protein 2, and it was never directly linked to cancer or EMT. We also identified U3 small nucleolar RNA-associated protein 25 homolog (UTP25), an understudied nucleolar protein, as one of AAK1’s interacting partners. We showed that the depletion of UTP25, like AAK1, produced phenotypes that are consistent with EMT reversal. Finally, through our investigation of AAK1’s functional relationship with UTP25, we discovered that AAK1 can localize to the nucleus, and that this nuclear localization may have isoform-specific preference.