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

Authors
  • Chan, Tsz-Yin
  • Egbert, Christina M
  • Maxson, Julia E
  • Siddiqui, Adam
  • Larsen, Logan J
  • Kohler, Kristina
  • Balasooriya, Eranga Roshan
  • Pennington, Katie L
  • Tsang, Tsz-Ming
  • Frey, Madison
  • Soderblom, Erik J
  • Geng, Huimin
  • Müschen, Markus
  • Forostyan, Tetyana V
  • Free, Savannah
  • Mercenne, Gaelle
  • Banks, Courtney J
  • Valdoz, Jonard
  • Whatcott, Clifford J
  • Foulks, Jason M
  • And 8 more
Publication Date
Jan 01, 2021
Source
eScholarship - University of California
Keywords
License
Unknown
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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.

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