AG490, a JAK2-specific inhibitor, downregulates the expression and activity of organic anion transporter-3.
AG490, a JAK2-specific inhibitor, downregulates the expression and activity of organic anion transporter-3.
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AG490，一种JAK2特异性抑制剂，下调有机阴离子转运蛋白3的表达和活性。
DOI：
10.1016/j.jphs.2018.01.006
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发表时间：
2018-03
影响因子：
3.5
通讯作者：
You G
中科院分区：
文献类型：
--
作者：
Zhang J;Liu C;You G
Human organic anion transporter-3 (hOAT3) is richly expressed in the kidney, where it plays critical roles in the secretion of clinically important drugs, including anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. In the current study, we examined the role of AG490, a specific inhibitor of the Janus tyrosine kinase 2 (JAK2), in hOAT3 transport activity in the kidney COS-7 cells. AG490 induced a time- and concentration-dependent inhibition of hOAT3-mediated uptake of estrone sulfate, a prototypical substrate for the transporter. The inhibitory effect of AG490 correlated with a reduced expression of hOAT3 at the cell surface. Our lab previously demonstrated that Nedd4-2, a ubiquitin ligase, down regulates OAT expression and transport activity by enhancing OAT ubiquitination, which leads to an internalization of OAT from cell surface to intracellular compartments and subsequent degradation. In the current study, we showed that treatment of hOAT3-expressing cells with AG490 resulted in an enhanced hOAT3 ubiquitination and degradation, which was accompanied by a strengthened association of Nedd4-2 with hOAT3 and a reduction in Nedd4-2 phosphorylation. SiRNA knockdown of endogenous Nedd4-2 abrogated the effects of AG490 on hOAT3. In summary, our study demonstrated that AG490 regulates hOAT3 expression and transport activity through the modulation of Nedd4-2.
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影响因子：
5
作者：
Duan, Peng;Li, Shanshan;You, Guofeng
通讯作者：
You, Guofeng
影响因子：
2.1
作者：
Wang H;You G
通讯作者：
You G
DOI：
10.1152/ajprenal.00272.2005
发表时间：
2006-04-01
影响因子：
4.2
作者：
Erdman, AR;Mangravite, LM;Giacomini, KM
通讯作者：
Giacomini, KM
影响因子：
4
作者：
Rawlings, JS;Rosler, KM;Harrison, DA
通讯作者：
Harrison, DA
DOI：
10.1097/01.asn.0000109672.83594.02
发表时间：
2004-02-01
影响因子：
13.6
作者：
Nakajima, H;Takenaka, M;Imai, E
通讯作者：
Imai, E