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; Navjotsingh Pabla

doi:10.1038/ncomms10880

A phosphotyrosine switch regulates organic cation transporters

Nat Commun. 2016 Mar 16:7:10880. doi: 10.1038/ncomms10880.

Authors

Jason A Sprowl¹, Su Sien Ong², Alice A Gibson³, Shuiying Hu³, Guoqing Du⁴, Wenwei Lin², Lie Li⁵, Shashank Bharill⁶, Rachel A Ness⁵, Adrian Stecula⁷, Steven M Offer⁸, Robert B Diasio⁸, Anne T Nies^{9

10}, Matthias Schwab^{9

11}, Guido Cavaletti¹², Eberhard Schlatter¹³, Giuliano Ciarimboli¹³, Jan H M Schellens¹⁴, Ehud Y Isacoff⁶, Andrej Sali^{7

15

16}, Taosheng Chen², Sharyn D Baker³, Alex Sparreboom³, Navjotsingh Pabla³

Affiliations

¹ Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York 14201, USA.
² Department of Chemical Biology &Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
³ Division of Pharmaceutics, College of Pharmacy &Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
⁴ Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
⁵ Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
⁶ Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
⁷ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158, USA.
⁸ Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota 55905, USA.
⁹ Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
¹⁰ University of Tuebingen, 72074 Tuebingen, Germany.
¹¹ Department of Clinical Pharmacology, University Hospital, 72076 Tuebingen, Germany.
¹² Department of Surgery and Translational Medicine, University of Milano-Bicocca, 20900 Monza, Italy.
¹³ Medical Clinic D, Experimental Nephrology and Interdisciplinary Center for Clinical Research (IZKF), Münster Medical Faculty, 48149 Münster, Germany.
¹⁴ Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
¹⁵ California Institute for Quantitative Biosciences, University of California, San Franscisco, California 94720, USA.
¹⁶ Department of Pharmaceutical Chemistry, University of California, San Franscisco, California 94158, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Ganglia, Spinal / drug effects
HEK293 Cells
HeLa Cells
Humans
Liver-Specific Organic Anion Transporter 1
Mice
Models, Molecular
Organic Anion Transporters / drug effects
Organic Anion Transporters / metabolism
Organic Cation Transport Proteins / drug effects*
Organic Cation Transport Proteins / metabolism
Organic Cation Transporter 1 / drug effects
Organic Cation Transporter 1 / metabolism
Organic Cation Transporter 2
Organoplatinum Compounds / pharmacology
Oxaliplatin
Phosphotyrosine / drug effects*
Phosphotyrosine / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / drug effects
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins c-yes / drug effects*
Proto-Oncogene Proteins c-yes / metabolism

Substances

Antineoplastic Agents
Liver-Specific Organic Anion Transporter 1
Organic Anion Transporters
Organic Cation Transport Proteins
Organic Cation Transporter 1
Organic Cation Transporter 2
Organoplatinum Compounds
Protein Kinase Inhibitors
SLC22A2 protein, human
SLC47A1 protein, human
SLCO1B1 protein, human
solute carrier family 22 (organic cation transporter), member 3
Oxaliplatin
Phosphotyrosine
Protein-Tyrosine Kinases
Proto-Oncogene Proteins c-yes
YES1 protein, human
Yes1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding