1区 · 综合性期刊
ArticleOA
作者: Whatcott, Clifford J ; Huang, David C S ; Valdoz, Jonard ; Banks, Courtney J ; Pennington, Katie L ; Egbert, Christina M ; Tsang, Tsz-Ming ; Siddiqui, Adam ; Balasooriya, Eranga Roshan ; Mercenne, Gaelle ; Tyner, Jeffrey W ; Maxson, Julia E ; Free, Savannah ; Müschen, Markus ; Moody, James ; Forostyan, Tetyana V ; Warner, Steven L ; Bearss, David J ; Larsen, Logan J ; Foulks, Jason M ; Geng, Huimin ; Christensen, Kenneth A ; Soderblom, Erik J ; Frey, Madison ; O'Hare, Thomas ; Kohler, Kristina ; Andersen, Joshua L ; Chan, Tsz-Yin
AbstractTNK1 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.
