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Influence of YES1 kinase and tyrosine phosphorylation on the activity of OCT1

Citation

Uddin, Muhammad Erfan et al. (2021), Influence of YES1 kinase and tyrosine phosphorylation on the activity of OCT1 , Dryad, Dataset, https://doi.org/10.5061/dryad.xsj3tx9dq

Abstract

Organic cation transporter 1 (OCT1) is a transporter that regulates the hepatic uptake and subsequent elimination of diverse cationic compounds. Although OCT1 has been involved in drug-drug interactions and causes pharmacokinetic variability of many prescription drugs, details of the molecular mechanisms that regulate the activity of OCT1 remain incompletely understood. Based on an unbiased phospho-proteomics screen, we identified OCT1 as a tyrosine-phosphorylated transporter, and functional validation studies using genetic and pharmacological approaches revealed that OCT1 is highly sensitive to small molecules that target the protein kinase YES1, such as dasatinib. In addition, we found that dasatinib can inhibit hepatic OCT1 function in mice as evidenced from its ability to modulate levels of isobutyryl L-carnitine, a hepatic OCT1 biomarker identified from a targeted metabolomics analysis. These findings provide novel insight into the post-translational regulation of OCT1 and suggest that caution is warranted with polypharmacy regimes involving the combined use of OCT1 substrates and kinase inhibitors that target YES1.

Methods

The tyrosine-phosphorylation landscape of ADME proteins was evaluated in FVB mice with the genetic deletion of OCT1/2 transporters using LC-MS/MS.

Usage Notes

The dataset contains both liver metabolomics (males and females), and phosphotyrosine proteomics data from kidney samples. In the liver metabolic data, certain cells are marked as red color which represents p-values <0.05. 

 

Funding

American Heart Association, Award: 20PRE35200228

National Institutes of Health, Award: P30CA016058

National Institutes of Health, Award: 0CA016058 (GSR), R01CA215802 (AS), and