A phosphotyrosine switch regulates organic cation transporters.
A phosphotyrosine switch regulates organic cation transporters.
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DOI：
10.1038/ncomms10880
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发表时间：
2016-03-16
影响因子：
16.6
通讯作者：
Pabla N
中科院分区：
文献类型：
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作者：
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 JHM;Isacoff EY;Sali A;Chen T;Baker SD;Sparreboom A;Pabla N
膜转运蛋白是治疗结果的关键决定因素。它们调节影响疗效和毒性的全身和细胞药物水平。在这里，我们报告了一个独特的磷酸化依赖的药物转运蛋白和酪氨酸激酶抑制剂（TKI）之间的相互作用，这已经发现了广泛的磷酸酪氨酸介导的调节药物转运蛋白。我们最初发现有机阳离子转运蛋白（OCT），二甲双胍和奥沙利铂的摄取载体，被几种临床使用的TKI抑制。机制研究表明，这些TKI抑制Src家族激酶Yes 1，发现其对OCT 2酪氨酸磷酸化和功能至关重要。体内Yes 1抑制降低了OCT 2活性，显著减轻了奥沙利铂诱导的急性感觉神经病变。沿着OCT 2，其他SLC家族药物转运蛋白可能是对TKI具有独特易感性的广泛“转运蛋白-磷酸化蛋白质组”的一部分。基于这些发现，我们认为TKI是一种重要且迅速扩展的治疗药物，可以通过抑制对翻译后调节至关重要的蛋白激酶来功能性调节重要蛋白。 有机阳离子转运蛋白是影响药物疗效的重要药物转运蛋白。在这里，作者发现这些转运蛋白受到酪氨酸磷酸化的调节，并提出酪氨酸激酶抑制剂可以通过翻译后机制影响药物转运蛋白功能。
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. Organic cation transporters are important drug transporters that influence therapeutic outcomes. Here, the authors find that these transporters are regulated by tyrosine phosphorylation and propose that tyrosine kinase inhibitors can influence drug transporter function through post-translational mechanisms.