TY - JOUR
T1 - Influence of YES1 Kinase and Tyrosine Phosphorylation on the Activity of OCT1
AU - Uddin, Muhammad Erfan
AU - Garrison, Dominique A.
AU - Kim, Kyeongmin
AU - Jin, Yan
AU - Eisenmann, Eric D.
AU - Huang, Kevin M.
AU - Gibson, Alice A.
AU - Hu, Zeping
AU - Sparreboom, Alex
AU - Hu, Shuiying
N1 - Funding Information:
This project was supported in part by AHA grant 20PRE35200228 (MU), NIH grants P30CA016058 (GSR), R01CA215802 (AS), and R01CA238946 (SH), and the Comprehensive Cancer Center at the Ohio State University using Pelotonia funds (KH). The content is solely the responsibility of the authors and does not represent the official views of the funding agencies.
Publisher Copyright:
© Copyright © 2021 Uddin, Garrison, Kim, Jin, Eisenmann, Huang, Gibson, Hu, Sparreboom and Hu.
PY - 2021/3/8
Y1 - 2021/3/8
N2 - 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.
AB - 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.
KW - YES1 kinase
KW - drug-transporter interactions
KW - organic cation transporter 1
KW - post-translational modification
KW - tyrosine kinase inhibitors
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U2 - 10.3389/fphar.2021.644342
DO - 10.3389/fphar.2021.644342
M3 - Article
C2 - 33790797
AN - SCOPUS:85103412701
SN - 1663-9812
VL - 12
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 644342
ER -