A phosphotyrosine switch regulates organic cation transporters

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

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
  • MATE1 protein, human
  • Organic Anion Transporters
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 1
  • Organic Cation Transporter 2
  • Organoplatinum Compounds
  • Protein Kinase Inhibitors
  • SLC22A2 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