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 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
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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U2 - 10.1038/s41467-021-25622-3
DO - 10.1038/s41467-021-25622-3
M3 - Article
C2 - 34504101
AN - SCOPUS:85114775400
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5337
ER -