TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth
- Chan, TY; Egbert, CM; Maxson, JE; Siddiqui, A; Larsen, LJ; Kohler, K; Balasooriya, ER; Pennington, KL; Tsang, TM; Frey, M; Soderblom, EJ; Geng, H; Müschen, M; Forostyan, TV; Free, S; Mercenne, G; Banks, CJ; Valdoz, J; Whatcott, CJ; Foulks, JM; Bearss, DJ; O'Hare, T; Huang, DCS; Christensen, KA; Moody, J; Warner, SL; Tyner, JW; Andersen, JL;
Publication Year 2021-09-09, Volume 12, Issue #1, Page 5337
- Journal Title
- Nature Communications
- 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
- Publisher's Version
- Open Access at Publisher's Site
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Creation Date: 2021-09-17 11:23:06Last Modified: 2021-09-17 11:30:51