Proteomic characterization of human kinases across tissue types: Implications for kinase-activated drugs

Kinases catalyze the activation of certain nucleoside and nucleotide analog drugs used in the treatment of various cancers and viral infections. Because these drugs require intracellular phosphorylation to their active form, the abundance of kinases within tissues is a key factor in determining both variability in response and off-target effects. In this study, we quantified and compared protein abundances of kinases in commercially available pooled S9 fractions of adult human liver (n = 50), kidney (n = 12), lung (n = 5), intestine (n = 4), and individual adult primary hepatocytes (n = 8). These data were compared with the proteomic abundance profile of red blood cells (n = 4) from healthy donors and bone marrow samples (n = 44) from patients with acute myeloid leukemia, in addition to kinase abundance in human plasma from the publicly available data base Human Protein Atlas. Kinase protein abundance was estimated using the total protein approach in pmol/mg total protein. We detected 364 kinases, including 23 drug-metabolizing kinases, with varying abundances across tissue and biofluid types. Four drug-metabolizing kinases, adenosine kinase, cytidine/uridine monophosphate kinase 1, and nucleoside diphosphate kinases 1 and 3, were detected in all sample types. In addition, by comparing tissue-to-plasma abundance ratios of kinases with those of known secreted versus nonsecreted marker proteins, we showed that kinases are primarily present in plasma due to tissue shedding, with few (phosphoglycerate kinase 1, pyruvate kinase M, adenylate kinase 1, and nucleoside diphosphate kinase 1) that may be present as part of extracellular vesicles. Lastly, we identified the presence of 24 kinases commonly targeted by inhibitors across sample types. Overall, this study advances the understanding of the presence and variability of kinases in different tissues. SIGNIFICANCE STATEMENT: This study quantified and compared the presence and abundance of kinases, including drug-metabolizing kinases, across various human sample types. In total, 364 kinases, including 23 known drug-metabolizing kinases, were detected with varying abundances across tissue and biofluid types. This study provides important quantitative data about drug-metabolizing kinases that can be used to understand variability in response and the off-target effects of nucleoside analog drugs.