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. Foulks, David J. Bearss, Thomas O’Hare, David C. S. Huang, Kenneth A. Christensen, James Moody, Steven L. Warner, Jeffrey W. Tyner and Joshua L. Andersen ()
Additional contact information
Tsz-Yin Chan: Brigham Young University
Christina M. Egbert: Brigham Young University
Julia E. Maxson: Oregon Health & Science University
Adam Siddiqui: Sumitomo Dainippon Pharma Oncology
Logan J. Larsen: Brigham Young University
Kristina Kohler: Brigham Young University
Eranga Roshan Balasooriya: Brigham Young University
Katie L. Pennington: Brigham Young University
Tsz-Ming Tsang: Brigham Young University
Madison Frey: Brigham Young University
Erik J. Soderblom: Duke University School of Medicine
Huimin Geng: University of California San Francisco
Markus Müschen: City of Hope Comprehensive Cancer Center
Tetyana V. Forostyan: Sumitomo Dainippon Pharma Oncology
Savannah Free: Sumitomo Dainippon Pharma Oncology
Gaelle Mercenne: Sumitomo Dainippon Pharma Oncology
Courtney J. Banks: Brigham Young University
Jonard Valdoz: Brigham Young University
Clifford J. Whatcott: Sumitomo Dainippon Pharma Oncology
Jason M. Foulks: Sumitomo Dainippon Pharma Oncology
David J. Bearss: Sumitomo Dainippon Pharma Oncology
Thomas O’Hare: University of Utah
David C. S. Huang: The Walter and Eliza Hall Institute of Medical Research
Kenneth A. Christensen: Brigham Young University
James Moody: Brigham Young University
Steven L. Warner: Sumitomo Dainippon Pharma Oncology
Jeffrey W. Tyner: Oregon Health & Science University
Joshua L. Andersen: Brigham Young University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25622-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25622-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25622-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().