Journal article
A phosphotyrosine switch regulates organic cation transporters
Nature communications, Vol.7(1), pp.10880-10880
03/16/2016
DOI: 10.1038/ncomms10880
PMCID: PMC4799362
PMID: 26979622
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.
Details
- Title: Subtitle
- A phosphotyrosine switch regulates organic cation transporters
- Creators
- Jason A. Sprowl - D'Youville CollegeSu Sien Ong - St. Jude Children's Research HospitalAlice A. Gibson - The Ohio State UniversityShuiying Hu - The Ohio State UniversityGuoqing Du - St. Jude Children's Research HospitalWenwei Lin - St. Jude Children's Research HospitalLie Li - St. Jude Children's Research HospitalShashank Bharill - University of California, BerkeleyRachel A. Ness - St. Jude Children's Research HospitalAdrian Stecula - University of California, San FranciscoSteven M. Offer - Mayo ClinicRobert B. Diasio - Mayo ClinicAnne T. Nies - Dr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyMatthias Schwab - Dr. Margarete Fischer-Bosch-Institute of Clinical PharmacologyGuido Cavaletti - University of Milano-BicoccaEberhard Schlatter - Munster Med Fac, Med Clin D, Expt Nephrol, D-48149 Munster, GermanyGiuliano Ciarimboli - Munster Med Fac, Med Clin D, Expt Nephrol, D-48149 Munster, GermanyJan H. M. Schellens - Oncode InstituteEhud Y. Isacoff - University of California, BerkeleyAndrej Sali - University of California, San FranciscoTaosheng Chen - St. Jude Children's Research HospitalSharyn D. Baker - The Ohio State UniversityAlex Sparreboom - The Ohio State UniversityNavjotsingh Pabla - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.7(1), pp.10880-10880
- Publisher
- Springer Nature
- DOI
- 10.1038/ncomms10880
- PMID
- 26979622
- PMCID
- PMC4799362
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Number of pages
- 11
- Grant note
- R01CA151633; P30CA021765; R25CA023944; R01CA138744; R01CA187176 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Robert-Bosch foundation, Stuttgart, Germany American Lebanese Syrian Associated Charities; American Lebanese Syrian Associated Charities (ALSAC) ICEPHA grant, Tuebingen-Stuttgart, Germany R01CA151633; R01CA187176; R01CA138744 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) P30CA021765 / US Public Health Service; United States Department of Health & Human Services; United States Public Health Service Cia2/013/13 / Interdisciplinary Center for Clinical Research Munster
- Language
- English
- Date published
- 03/16/2016
- Academic Unit
- Pathology
- Record Identifier
- 9984618521102771
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