TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth

• DOI: 10.1038/s41467-021-25622-3
• Publication Date: 2021-09-09T10:05:22Z
• Authors: Tsz-Yin Chan; Christina M. Egbert; Julia E. Maxson; Adam Siddiqui; Logan J. Larsen; Kristina Kohler; Eranga Roshan Bal...; Katie L. Pennington; Tsz-Ming Tsang; Madison Frey; Erik J. Soderblom; Huimin Geng; Markus Müschen; Tetyana V. Forostyan; Savannah Free; Gaelle Mercenne; Courtney J. Banks; Jonard Valdoz; Clifford J. Whatcott; Jason M. Foulks; David J. Bearss; Thomas O’Hare; David C. S. Huang; Kenneth A. Christ...; James Moody; Steven L. Warner; Jeffrey W. Tyner; Joshua L. Andersen
• Keywords: Fetal Proteins; STAT3 Transcription Factor; 0301 basic medicine; Science; bcr-abl; Fusion Proteins, bcr-abl; 610; Antineoplastic Agents; Article; Cell Line; Mice; 03 medical and health sciences; Cell Line, Tumor; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; STAT5 Transcription Factor; 2.1 Biological and endogenous factors; Animals; Humans; Lymphocytes; Aetiology; Protein Kinase Inhibitors; Cancer; Neoplastic; 0303 health sciences; Tumor; Biomedical and Clinical Sciences; Ubiquitin; Phospholipase C gamma; Q; Fusion Proteins; Biological Sciences; Protein-Tyrosine Kinases; Survival Analysis; Xenograft Model Antitumor Assays; Tumor Burden; 3. Good health; Gene Expression Regulation, Neoplastic; HEK293 Cells; Pyrimidines; Gene Expression Regulation; 14-3-3 Proteins; A549 Cells; Biochemistry and Cell Biology; Signal Transduction; Protein Binding

AbstractTNK1 is a non-receptor tyrosine kinase with poorly understood biological function and regulation. Here, we identify TNK1 dependencies in primary human cancers. We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity. Conversely, the release of TNK1 from 14-3-3 allows TNK1 to cluster in ubiquitin-rich puncta and become active. Active TNK1 induces growth factor-independent proliferation of lymphoid cells in cell culture and mouse models. One unusual feature of TNK1 is a ubiquitin-association domain (UBA) on its C-terminus. Here, we characterize the TNK1 UBA, which has high affinity for poly-ubiquitin. Point mutations that disrupt ubiquitin binding inhibit TNK1 activity. These data suggest a mechanism in which TNK1 toggles between 14-3-3-bound (inactive) and ubiquitin-bound (active) states. Finally, we identify a TNK1 inhibitor, TP-5801, which shows nanomolar potency against TNK1-transformed cells and suppresses tumor growth in vivo.