Posttranslational Regulation of Organic Anion Transporters by Ubiquitination: Known and Novel

Abstract

Synopsis Organic anion transporters (OATs) encoded by solute carrier 22 (SLC22) family are localized in the epithelia of multiple organs, where they mediate the absorption, distribution, and excretion of a diverse array of negatively charged environmental toxins and clinically important drugs. Alterations in the expression and function of OATs play important roles in intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs. As a result, the activity of OATs must be under tight regulation so as to carry out their normal functions. The regulation of OAT transport activity in response to various stimuli can occur at several levels such as transcription, translation, and posttranslational modification. Posttranslational regulation is of particular interest, because it usually happens within a very short period of time (minutes to hours) when the body has to deal with rapidly changing amounts of substances as a consequence of variable intake of drugs, fluids, or meals as well as metabolic activity. This review article highlights the recent advances from our laboratory in uncovering several posttranslational mechanisms underlying OAT regulation. These advances offer the promise of identifying targets for novel strategies that will maximize therapeutic efficacy in drug development.

Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets

“…KEGG pathway analysis of the top 10-downregulated genes was limited by the lack of data in both species, with data reported for only two genes, GRTP1 and SLC5A5, which demonstrated 100 and 11% similarity, respectively. Genes in the top 10 downregulated category are found to act as tumor suppressors [SMCO2 (51), CCBE1 (50)], increase responsiveness to chemotherapy [SLC22A6 (52–54), SLC5A5 (55)], serve as prognostic markers [CCBE1 (56)], and play a role in cellular differentiation [KRT24 (57), CCBE1 (50)]. In other cancers, decreased expression of these genes has been associated with vascular invasion and increased tumor aggressiveness [SLC5A5/NIS (58)], increased proliferation [SMOC2 (51)], increased migration [SMOC2 (51), CCBE1 (59, 60)], and poor prognosis [ECEL (61)].…”

The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease

“…Over the years, a considerable amount of data have accumulated on the intersection of transporters with signaling and sorting pathways, and this is true of SLC22 transporters as well (109, 110). These transporters undergo covalent modifications, such as phosphorylation, including tyrosine phosphorylation by Src family kinases, which can affect OCT function (111).…”

Proteasome Inhibitors Bortezomib and Carfilzomib Stimulate the Transport Activity of Human Organic Anion Transporter 1

“…We further demonstrated that activation of protein kinase C (PKC) inhibits OAT1 transport activity and reduces the amount of OAT1 at the cell surface by enhancing OAT1 ubiquitination, resulting an accelerated OAT1 internalization from cell surface to intracellular early endosomes and subsequent proteolytic degradation Zhang et al, 2008;Zhang et al, 2013). Ubiquitination is an important post-translational mechanism of OAT1 regulation (Xu et al, 2016a;.…”

“…followed by the efflux of these drugs to urine by other transporters in the apical membrane (Nigam, 2015;Xu et al, 2016a;You, 2002). The function of OAT1 is the rate-limiting factor in the renal clearance of drugs from the body, affecting drug concentration in the plasma and various tissues, thereby influencing drug therapeutic efficacy and the toxicity.…”