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TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth

Nat Commun. 2021-09; 
Tsz-Yin Chan, Christina M Egbert, Julia E Maxson, Adam Siddiqui, Logan J Larsen, Kristina Kohler, Eranga Roshan Balasooriya, Katie L Pennington, Tsz-Ming Tsang, Madison Frey, Erik J Soderblom, Huimin Geng, Markus Müschen, Tetyana V Forostyan, Savannah Free, Gaelle Mercenne, Courtney J Banks, Jonard Valdoz, Clifford J Whatcott, Jason M Foulks, David J Bearss, Thomas O'Hare, David C S Huang, Kenneth A Christensen, James Moody, Steven L Warner, Jeffrey W Tyner, Joshua L Andersen
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Mutagenesis Services … FLAG-TNK1 expression plasmid was purchased from GenScript. All mutagenesis was performed using the Q5 Site-Directed Mutagenesis Kit (NEB), following the manufacturer’s protocol. A complete list of all primers used is included in a table in Supplementary Information. … Get A Quote

摘要

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-ubiqui... More

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