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

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
DOI: 10.1038/s41467-021-25622-3 Publication Date: 2021-09-09T10:05:22Z
ABSTRACT
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.
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