Protein Kinases and Cross-talk between Post-translational Modifications in the Regulation of Drug Transporters

Drug transporters are modulators for drug absorption, distribution, and excretion. Key drug transporters including P-glycoprotein and breast cancer resistance protein of the ABC superfamily; organic anion transporting polypeptide 1B1 and 1B3, organic anion trans-porter 1 and 3, and organic cation transporter 2, as well as multi-drug and toxin extrusion 1 and 2 of the SLC superfamily have been recommended by regulatory agencies to be investigated and eval-uated in drug-drug interaction (DDI) studies due to their important roles in determining the efficacy, toxicity and DDI of various drugs. Drug transporters are subjected to multiple levels of control and post-translational modifications (PTMs) provide rapid and versatile ways of regulation. Under pathologic and/or pharmacological con-ditions, PTMs may be altered in the cellular system, leading to func-tional changes of transporter proteins. Phosphorylation is by far the most actively investigated form of PTMs in the regulation of ttransporters. Further, studies in recent years also found that protein kinases coordinate with other PTMs for the dynamic control of these membrane proteins. Here we summarized the regulation of major drug transporters by protein kinases and their cross-talking with other PTMs that may generate a complex regulatory network for fine-tuning the function of these important drug processing modulators.SIGNIFICANCE STATEMENT Kinases regulate drug transporters in versatile manners; Kinase regulation cross-talks with other PTMs, forming a complex net -work for transporter regulation; Pathological and/or pharmaco-logical conditions may alter PTMs and affect transporter function with different molecular mechanisms.