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

Fetal Proteins STAT3 Transcription Factor 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
Abstract TNK1 is a non-receptor tyrosine kinase with poorly understood biological function and regulation. Here, we identify dependencies in primary human cancers. We also discover MARK-mediated phosphorylation on at S502 that promotes an interaction between 14-3-3, which sequesters inhibits its activity. Conversely, the release of from 14-3-3 allows to cluster ubiquitin-rich puncta become active. Active induces growth factor-independent proliferation lymphoid cells cell culture mouse models. One unusual feature ubiquitin-association domain (UBA) C-terminus. characterize UBA, has high affinity for poly-ubiquitin. Point mutations disrupt ubiquitin binding inhibit These data suggest mechanism toggles 14-3-3-bound (inactive) ubiquitin-bound (active) states. Finally, inhibitor, TP-5801, shows nanomolar potency against TNK1-transformed suppresses tumor vivo.
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