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
  • 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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