(507.7) TNK1 is a ubiquitin-sensing kinase that can be targeted to block tumor growth

Poster Board Number: A311

Joshua Andersen (Brigham Young University), Tsz-Yin Chan (Brigham Young University), Christina Egbert (Brigham Young University), Tania Lopez-Palacios (Brigham Young University), Julia Maxson (Oregon Health Sciences University), Jeffrey Tyner (Oregon Health Sciences University), Steven Warner (Sumitomo Dainippon Pharma Oncology)

Thirty-eight negative kinase-1 (TNK1) is an understudied non-receptor tyrosine kinase with no established function or mechanism of regulation. We recently identified TNK1 as the primary kinase driver of cell survival in subsets of patient blood cancer samples1. We discovered that one unusual feature of TNK1 is a functional ubiquitin-association (UBA) domain that binds with high affinity to multiple poly-ubiquitin linkages. Our recent 1.5 angstrom crystal structure of the TNK1 UBA shows an atypical five-helix UBA domain with two predicted ubiquitin-binding interfaces. We found that TNK1 relies on its UBA domain to home to phase-separated poly-ubiquitylated protein condensates and becomes fully active at these sites. To our knowledge, this feature of TNK1—a bona-fide ubiquitin-association domain that promotes kinase activation—makes TNK1 unique across the human kinome. Our data also suggest that 14-3-3 interacts with a MARK-mediated phosphorylation at S502 of TNK1 to sequester the kinase away from ubiquitin and inhibit kinase activation. Thus, TNK1 toggles between poly-ubiquitin bound (active) and 14-3-3-bound (inactive) states. Our preliminary data suggest that the interaction with poly-ubiquitin at condensates tethers TNK1 to substrates, facilitating its phosphorylation of substrates involved in the lysosomal degradation of condensates. Furthermore, we found that patient mutations that truncate the 14-3-3 binding site and UBA domain convert TNK1 into a cancer driver with an altered substrate profile, skewed toward pro-growth substrates like STAT3. Finally, we show that mutant TNK1-driven tumors can be targeted in vivo with a novel anti-TNK1 small molecule. Thus, together our data suggest that TNK1 acts as a ubiquitin sensor and is a candidate for targeted therapy. 

1. Chan TY and Egbert CM et al., (2021) TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth. Nature Communications (in press)

American Cancer Society Research Scholar Grant 133550-RSG-19-006-01-CCG