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.
authors.affiliation: Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York 14201, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Sprowl
authors.affiliation: Department of Chemical Biology &Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Su Sien
authors.initials: SS
authors.lastname: Ong
authors.affiliation: Division of Pharmaceutics, College of Pharmacy &Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Alice A
authors.initials: AA
authors.lastname: Gibson
authors.affiliation: Division of Pharmaceutics, College of Pharmacy &Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Du
authors.affiliation: Department of Chemical Biology &Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Bharill
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ness
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Stecula
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota 55905, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Offer
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota 55905, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.|University of Tuebingen, 72074 Tuebingen, Germany.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nies
authors.affiliation: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.|Department of Clinical Pharmacology, University Hospital, 72076 Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900 Monza, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.affiliation: Medical Clinic D, Experimental Nephrology and Interdisciplinary Center for Clinical Research (IZKF), Münster Medical Faculty, 48149 Münster, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlatter
authors.affiliation: Medical Clinic D, Experimental Nephrology and Interdisciplinary Center for Clinical Research (IZKF), Münster Medical Faculty, 48149 Münster, Germany.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciarimboli
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jan H M
authors.initials: JHM
authors.lastname: Schellens
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
authors.forename: Ehud Y
authors.initials: EY
authors.lastname: Isacoff
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158, USA.|California Institute for Quantitative Biosciences, University of California, San Franscisco, California 94720, USA.|Department of Pharmaceutical Chemistry, University of California, San Franscisco, California 94158, USA.
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.affiliation: Department of Chemical Biology &Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.affiliation: Division of Pharmaceutics, College of Pharmacy &Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.affiliation: Division of Pharmaceutics, College of Pharmacy &Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.affiliation: Division of Pharmaceutics, College of Pharmacy &Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Navjotsingh
authors.initials: N
authors.lastname: Pabla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D008958:Models, Molecular; D027361:Organic Anion Transporters / Q000187:drug effects / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000187:drug effects / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D019000:Phosphotyrosine / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000187:drug effects* / Q000378:metabolism; D000099254:Organic Cation Transporter 3
chemical_list: D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019000:Phosphotyrosine; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D051575:Proto-Oncogene Proteins c-yes; D000099254:Organic Cation Transporter 3; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C503999:SLCO1B1 protein, human; C489834:YES1 protein, human; C496639:Yes1 protein, mouse