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Thirty-eight-negative kinase 1 (TNK1) is a poorly understood member of the ACK family of non-receptor tyrosine kinases. TNK1 has been linked to oncogenic activity (Hoare, 2008; Lierman, 2009; Gu, 2010) and inflammatory signaling (Bao, 2020), but its substrates, regulation, and normal biological function remain mostly uncharacterized. Recently, we discovered that TNK1 has a functional ubiquitin association (UBA) domain on its C-terminus that interacts with diverse linkages of poly-ubiquitin. Interestingly, we also found that deletion of the TNK1 UBA domain alters TNK1 intracellular localization and decreases its phospho-substrate network (Chan and Egbert, 2021). Based on these data, we hypothesized that the UBA domain, via interaction with poly-ubiquitin, may tether TNK1 to substrates. To test this hypothesis, we used quantitative phospho-tyrosine proteomics in a cell model that relies on exogenous TNK1 for phospho-tyrosine signaling. Through this approach we identified the serine/threonine kinase TBK1 (Tank-binding kinase-1) among several putative UBA-dependent TNK1 substrates involved in inflammation and ubiquitin-related processes. Using custom site-specific pY antibodies, we validated a panel of these TNK1 substrates, including TBK1, and our work now incorporates hyperactive and inactive TNK1 knock-in mouse models and cell culture models to understand how TNK1 impacts these substrates to regulate stress and inflammatory signaling. This work was supported by the National Institutes of Health (NIGMS R01 GM147310-01).
Kohler et al. (Fri,) studied this question.