Serum- and glucocorticoid-inducible kinase SGK2 regulates human organic anion transporters 4 via ubiquitin ligase Nedd4-2

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• 作者：Haoxun Wang^a ; Da Xu^a ; May Fern Toh^a ; Alan C. Pao^b ; Guofeng You^a ; ^{gyou@rci.rutgers.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Organic anion transporter ; Drug transport ; Regulation ; Serum and glucocorticoid-inducible kinase ; Ubiquitin ligase ; Ubiquitination
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：102
• 期：Complete
• 页码：120-129
• 全文大小：1640 K

文摘

Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the kidney and placenta. In the current study, we examined the regulation of hOAT4 by serum- and glucocorticoid-inducible kinase 2 (sgk2) in the kidney COS-7 cells. We showed that sgk2 stimulated hOAT4 transport activity. Such stimulation mainly resulted from an increased cell surface expression of the transporter, kinetically revealed as an increased maximal transport velocity V_max without significant change in substrate-binding affinity K_m. We further showed that regulation of hOAT4 activity by sgk2 was mediated by ubiquitin ligase Nedd4-2. Overexpression of Nedd4-2 enhanced hOAT4 ubiquitination, and inhibited hOAT4 transport activity, whereas overexpression of ubiquitin ligase-dead mutant Nedd4-2/C821A or siRNA knockdown of endogenous Nedd4-2 had opposite effects on hOAT4. Our co-immunoprecipitation experiment revealed that sgk2 weakened the association between hOAT4 and Nedd4-2. In conclusion, our study demonstrated for the first time that sgk2 stimulated hOAT4 transport activity by abrogating the inhibitory effect of Nedd4-2 on the transporter.