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
AUTHORS (28)
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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