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
AUTHORS (28)
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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