TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth.
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.
Chan, T-Y; Egbert, CM; Maxson, JE; Siddiqui, A; Larsen, LJ; Kohler, K; Balasooriya, ER; Pennington, KL; Tsang, T-M; 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
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