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

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

  • Nat Commun. 2021 Sep 9;12(1):5337. doi: 10.1038/s41467-021-25622-3.
Tsz-Yin Chan  # 1 2,  Christina M Egbert  # 1 2,  Julia E Maxson 3 4,  Adam Siddiqui 5,  Logan J Larsen 1 2,  Kristina Kohler 1 2,  Eranga Roshan Balasooriya 1 2,  Katie L Pennington 1 2,  Tsz-Ming Tsang 2,  Madison Frey 1 2,  Erik J Soderblom 6,  Huimin Geng 7,  Markus Müschen 8,  Tetyana V Forostyan 5,  Savannah Free 5,  Gaelle Mercenne 5,  Courtney J Banks 1 2,  Jonard Valdoz 1 2,  Clifford J Whatcott 5,  Jason M Foulks 5,  David J Bearss 5,  Thomas O'Hare 9,  David C S Huang 10,  Kenneth A Christensen 2,  James Moody 2,  Steven L Warner 5,  Jeffrey W Tyner 3 4,  Joshua L Andersen 11 12
Affiliations

Affiliations

  • 1 Fritz B. Burns Cancer Research Laboratory, Brigham Young University, Provo, UT, USA.
  • 2 Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, USA.
  • 3 Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 4 Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 5 Sumitomo Dainippon Pharma Oncology, Lehi, UT, USA.
  • 6 Proteomics and Metabolomics Shared Resource, Duke University School of Medicine, Durham, NC, USA.
  • 7 Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
  • 8 Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA.
  • 9 Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake, City, UT, USA.
  • 10 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 11 Fritz B. Burns Cancer Research Laboratory, Brigham Young University, Provo, UT, USA. [email protected].
  • 12 Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, USA. [email protected].
  • # Contributed equally.
PMID: 34504101 DOI: 10.1038/s41467-021-25622-3
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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