SGK1/Nedd4-2 signaling pathway regulates the activity of human organic anion transporters 3.
SGK1/Nedd4-2 signaling pathway regulates the activity of human organic anion transporters 3.
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DOI：
10.1002/bdd.2085
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发表时间：
2017-11
影响因子：
2.1
通讯作者：
You G
中科院分区：
文献类型：
--
作者：
Wang H;You G
Human organic anion transporter 3 (hOAT3) is localized at the basolateral membrane of renal proximal tubule cells and facilitates renal secretion of numerous clinical drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, antihypertension drugs, and anti-inflammatories. In the present study, we explored the role of serum and glucocorticoid-inducible kinase 1 (sgk1) in the regulation of hOAT3. We showed that over-expression of sgk1 in hOAT3-expressing cells stimulated hOAT3 transport activity by enhancing the transporter expression at the plasma membrane, kinetically reflected as an increased maximal transport velocity Vmax without substantial change in substrate-binding affinity Km. In contrast, treatment of cells with sgk-specific inhibitor GSK650394 resulted in a dose-dependent inhibition of hOAT3 transport activity. We further provided evidence that sgk1 regulation of hOAT3 activity was mediated by ubiquitin ligase Nedd4-2, an enzyme previously shown to have inhibitory effect on hOAT3. We showed that sgk1 phosphorylated Nedd4-2, weakened the association between Nedd4-2 and hOAT3, and decreased hOAT3 ubiquitination. Functionally, sgk1-stimulated hOAT3 transport activity was attenuated in the presence of a ligase-dead mutant of Nedd4-2. In summary, our investigation established for the first time that sgk1 stimulates hOAT3 transport activity by interfering with the inhibitory effect of Nedd4-2 on the transporter.
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DOI：
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