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

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. FoulksDavid J. Bearss, Thomas O’Hare, David C.S. Huang, Kenneth A. Christensen, James Moody, Steven L. Warner, Jeffrey W. Tyner, Joshua L. Andersen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number5337
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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