Q1 · CROSS-FIELD
ArticleOA
Author: Banks, Courtney J ; Chan, Tsz-Yin ; Whatcott, Clifford J ; Siddiqui, Adam ; Andersen, Joshua L ; Maxson, Julia E ; Foulks, Jason M ; Balasooriya, Eranga Roshan ; Mercenne, Gaelle ; Müschen, Markus ; Tyner, Jeffrey W ; Valdoz, Jonard ; Bearss, David J ; Egbert, Christina M ; Larsen, Logan J ; Soderblom, Erik J ; O'Hare, Thomas ; Geng, Huimin ; Christensen, Kenneth A ; Tsang, Tsz-Ming ; Kohler, Kristina ; Pennington, Katie L ; Frey, Madison ; Moody, James ; Warner, Steven L ; Free, Savannah ; Huang, David C S ; Forostyan, Tetyana V
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.