A phosphotyrosine switch regulates organic cation transporters.
Sprowl JA, Ong SS, Gibson AA, Hu S, Du G, Lin W, Li L, Bharill S, Ness RA, Stecula A, Offer SM, Diasio RB, Nies AT, Schwab M, Cavaletti G, Schlatter E, Ciarimboli G, Schellens JH, Isacoff EY, Sali A, Chen T, Baker SD, Sparreboom A, Pabla N
Nat Commun 7 10880 03/16/2016
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.Full Text