TY - JOUR
T1 - TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth
AU - Chan, Tsz Yin
AU - Egbert, Christina M.
AU - Maxson, Julia E.
AU - Siddiqui, Adam
AU - Larsen, Logan J.
AU - Kohler, Kristina
AU - Balasooriya, Eranga Roshan
AU - Pennington, Katie L.
AU - Tsang, Tsz Ming
AU - Frey, Madison
AU - Soderblom, Erik J.
AU - Geng, Huimin
AU - Müschen, Markus
AU - Forostyan, Tetyana V.
AU - Free, Savannah
AU - Mercenne, Gaelle
AU - Banks, Courtney J.
AU - Valdoz, Jonard
AU - Whatcott, Clifford J.
AU - Foulks, Jason M.
AU - Bearss, David J.
AU - O’Hare, Thomas
AU - Huang, David C.S.
AU - Christensen, Kenneth A.
AU - Moody, James
AU - Warner, Steven L.
AU - Tyner, Jeffrey W.
AU - Andersen, Joshua L.
N1 - Funding Information:
We thank the Fritz B. Burns Foundation for student and postdoctoral salary support to LJL, KK, KLP, and critical instrumentation. We thank Drs. Erik Soderblom and Will Thompson at Duke University School of Medicine for the use of the Proteomics and Metabolomics Shared Resource, which provided TiO2 and pY proteomics data. We thank Dr. David Lum and colleagues from the Preclinical Research Resource (PRR) at the Huntsman Cancer Institute, which provided mice, surgical procedures, IVIS imaging, and histology service. We thank Tony Pomicter and members of Michael Deininger’s lab for key reagents and guidance on the project. We thank Drs. Rafael Casellas, Jens Kalchschmidt, as well as all members of the Casellas, Andersen, and David Huang labs for constructive discussion and scientific input. We thank Drs. Alana Welm, Grant Dewson, Mark van Delft, Denis Tvorgorov, Isabelle Lucet, and David Komander for technical assistance and insights into kinase/ubiquitin biology. We thank the Simmons Center for Cancer Research, Roland K. Robins, and the BYU College of Physical and Mathematical Sciences for graduate fellowships to TYC; and graduate studies for a HIDRA fellowship to CME. JEM is supported by an American Society of Hematology Scholar Award, American Cancer Society Research Scholar Grant RSG-19-184-01, a Lamfrom Laureate Award, and R00 CA190605 from the National Cancer Institute. JLA is supported by an American Cancer Society Research Scholar Grant (133550-RSG-19-006-01-CCG) (2019-current) and a National Cancer Institute/National Institutes of Health grant (2R15CA202618-02).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85114775400&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25622-3
DO - 10.1038/s41467-021-25622-3
M3 - Article
C2 - 34504101
AN - SCOPUS:85114775400
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5337
ER -