A phosphotyrosine switch regulates organic cation transporters

Jason A. Sprowl, Su Sien Ong, Alice A. Gibson, Shuiying Hu, Guoqing Du, Wenwei Lin, Lie Li, Shashank Bharill, Rachel A. Ness, Adrian Stecula, Steven M. Offer, Robert B. Diasio, Anne T. Nies, Matthias Schwab, Guido Cavaletti, Eberhard Schlatter, Giuliano Ciarimboli, Jan H. M. Schellens, Ehud Y. Isacoff, Andrej Sali, Taosheng Chen, Sharyn D. Baker, Alex Sparreboom () and Navjotsingh Pabla ()
Additional contact information
Jason A. Sprowl: Social and Administrative Sciences, School of Pharmacy, D’Youville College
Su Sien Ong: St Jude Children's Research Hospital
Alice A. Gibson: College of Pharmacy & Comprehensive Cancer Center, The Ohio State University
Shuiying Hu: College of Pharmacy & Comprehensive Cancer Center, The Ohio State University
Guoqing Du: St. Jude Children's Research Hospital
Wenwei Lin: St Jude Children's Research Hospital
Lie Li: St Jude Children's Research Hospital
Shashank Bharill: University of California
Rachel A. Ness: St Jude Children's Research Hospital
Adrian Stecula: University of California
Steven M. Offer: Mayo Clinic Cancer Center
Robert B. Diasio: Mayo Clinic Cancer Center
Anne T. Nies: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376
Matthias Schwab: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376
Guido Cavaletti: University of Milano-Bicocca
Eberhard Schlatter: Medical Clinic D, Experimental Nephrology and Interdisciplinary Center for Clinical Research (IZKF), Münster Medical Faculty
Giuliano Ciarimboli: Medical Clinic D, Experimental Nephrology and Interdisciplinary Center for Clinical Research (IZKF), Münster Medical Faculty
Jan H. M. Schellens: The Netherlands Cancer Institute
Ehud Y. Isacoff: University of California
Andrej Sali: University of California
Taosheng Chen: St Jude Children's Research Hospital
Sharyn D. Baker: College of Pharmacy & Comprehensive Cancer Center, The Ohio State University
Alex Sparreboom: College of Pharmacy & Comprehensive Cancer Center, The Ohio State University
Navjotsingh Pabla: College of Pharmacy & Comprehensive Cancer Center, The Ohio State University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10880

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