@article{4d778718eccd4381a26bd37bf481a75c,
title = "A phosphotyrosine switch regulates organic cation transporters",
abstract = "Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation.",
author = "Sprowl, {Jason A.} and Ong, {Su Sien} and Gibson, {Alice A.} and Shuiying Hu and Guoqing Du and Wenwei Lin and Lie Li and Shashank Bharill and Ness, {Rachel A.} and Adrian Stecula and Offer, {Steven M.} and Diasio, {Robert B.} and Nies, {Anne T.} and Matthias Schwab and Guido Cavaletti and Eberhard Schlatter and Giuliano Ciarimboli and Schellens, {Jan H.M.} and Isacoff, {Ehud Y.} and Andrej Sali and Taosheng Chen and Baker, {Sharyn D.} and Alex Sparreboom and Navjotsingh Pabla",
note = "Funding Information: We thank Kirti Bhatt (City of Hope, CA, USA), Craig R. Brooks (Harvard University, MA, USA), Barthelemy Diouf and John Lynch (St Jude Children{\textquoteright}s Research Hospital, TN, USA) for critical reading of the manuscript. We thank the members of the Sparreboom and Baker laboratories for assistance with experiments and helpful comments during manuscript preparation. We also thank Ashutosh Mishra and Anthony High (St Jude Children{\textquoteright}s Research Hospital, TN, USA) for providing assistance with proteomics experiments. This work was supported in part by the American Lebanese Syrian Associated Charities, National Cancer Institute Grants (R01CA151633, R01CA187176 and R01CA138744), US Public Health Service Grant (P30CA021765), Grant Cia2/013/13 from the Interdisciplinary Center for Clinical Research M{\"u}nster, the Robert-Bosch foundation, Stuttgart, Germany and the ICEPHA grant, Tuebingen-Stuttgart, Germany.",
year = "2016",
month = mar,
day = "16",
doi = "10.1038/ncomms10880",
language = "English (US)",
volume = "7",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}