TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth
Details
Publication Year 2021-09-09, Volume 12, Issue #1, Page 5337
Journal Title
Nature Communications
Abstract
TNK1 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.
WEHI Research Division(s)
Blood Cells And Blood Cancer
PubMed ID
34504101
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-021-25622-3
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2021-09-17 11:23:06
Last Modified: 2021-09-17 11:30:51
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