Phosphorylation of the Catalytic Subunit of Rat Renal Na+,K+-ATPase by Classical PKC Isoforms

Kazanietz, Marcelo G.; Caloca, Marı́a J.; Aizman, Oleg; Nowicki, Susana

doi:10.1006/abbi.2000.2264

Cited by 31 publications

(20 citation statements)

References 33 publications

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“…This is a result, at least in part, of restoration of Na ϩ /K ϩ -ATPase activity in RPTC treated with PKC-␣ and ERK1/2 inhibitors prior to cisplatin exposure. Thus, our results suggest that PKC-␣ and ERK1/2 regulate Na ϩ /K ϩ -ATPase activity in RPTC, which is consistent with a previous report showing that Ca 2ϩ -dependent isozymes of PKC phosphorylate catalytic ␣ 1 subunit of renal Na ϩ /K ϩ -ATPase and that this phosphorylation inhibits Na ϩ /K ϩ -ATPase activity (60).…”

Section: Discussionsupporting

confidence: 93%

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

Nowak

2002

Journal of Biological Chemistry

249

204

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Section: Discussionsupporting

confidence: 93%

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

Nowak

2002

Journal of Biological Chemistry

249

204

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“…First, these cells are of kidney origin and have been very useful in understanding other renal transport processes (Zhang et al, 2002;Nagai et al, 2006). Second, these cells possess endogenous PKC and PKA signaling pathways and provide a good experimental model system for studying the regulatory mechanisms underlying many transport processes (Kazanietz et al, 2001;Cobb et al, 2002). Lastly, the transport characteristics of OAT1 in these cells were in good agreement with that observed in other Fig.…”

Section: Discussionsupporting

confidence: 73%

Three Ubiquitination Sites of Organic Anion Transporter-1 Synergistically Mediate Protein Kinase C–Dependent Endocytosis of the Transporter

Li¹,

Zhang²,

You³

2013

Mol Pharmacol

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Organic anion transporter-1 (OAT1) mediates the body disposition of a diverse array of clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatories. Therefore, understanding the regulation of OAT1 has profound clinical significance. We previously established that OAT1 constitutively internalizes from and recycles back to cell surface and that activation of protein kinase C (PKC) inhibits OAT1 activity by promoting ubiquitination of the transporter, which then leads to an accelerated internalization of the transporter from cell surface to intracellular compartments. In the current study, we showed that PKC isoform PKCa was responsible for OAT1 ubiquitination. To directly address the role of OAT1 ubiquitination, we then generated two OAT1 mutants, each having multiple lysines (K) simultaneously mutated to arginine (R). One mutant K163/297/303/315/321R lost sensitivities to PKC-induced inhibition of transport activity, to PKC-induced ubiquitination, and to PKC-induced acceleration of transporter internalization. Further dissecting each lysine in this mutant, we identified Lys297, Lys303, and Lys315 as being the ubiquitin conjugation sites. Of interest, mutating any one of the three lysines prevented the ubiquitin conjugation to the other two lysines, suggesting that Lys297, Lys303, and Lys315 may form an optimal structure to interact with ubiquitination machineries. This is the first demonstration that Lys297, Lys303, and Lys315 play a synergistic role in PKC-regulated OAT1 ubiquitination, trafficking, and transport activity.

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“…system for studying the regulatory mechanisms underlying many transport processes (Cobb et al, 2002;Kazanietz et al, 2001). 4) The transport characteristics of OAT1 in COS-7 cells are in good agreement with those observed in other systems (Miller, 1998;Shuprisha et al, 2000;Zhang et al, 2008).…”

Section: Qledgrt +3supporting

confidence: 73%

Lysine 48-Linked Polyubiquitination of Organic Anion Transporter-1 Is Essential for Its Protein Kinase C–Regulated Endocytosis

Zhang

Patterson

et al. 2012

Mol Pharmacol

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Organic anion transporter-1 (OAT1) mediates the body's disposition of a diverse array of environmental toxins and clinically important drugs. Therefore, understanding the regulation of this transporter has profound clinical significance. We had previously established that OAT1 undergoes constitutive internalization from and recycling back to the cell surface and that acute activation of protein kinase C (PKC) inhibits OAT1 activity by reducing OAT1 cell-surface expression through accelerating its internalization from cell surface to intracellular compartments. However, the underlying mechanisms are poorly understood. In the current study, we provide novel evidence that acute activation of PKC significantly enhances OAT1 ubiquitination both in vitro and ex vivo. We further show that ubiquitination of cell-surface OAT1 increases in cells transfected with dominant negative mutant of dynamin-2, a maneuver blocking OAT1 internalization, which suggests that OAT1 ubiquitination proceeds before OAT1 internalization. Mass spectroscopy has revealed that ubiquitination of OAT1 consists of polyubiquitin chains, primarily through lysine 48 linkage. Transfection of cells with the dominant negative mutant of ubiquitin Ub-K48R, which prevents the formation of Lys48-linked polyubiquitin chains, abolishes PKC-stimulated OAT1 ubiquitination and internalization. Together, our findings demonstrate for the first time that Lys48-linked polyubiquitination is essential for PKC-regulated OAT1 trafficking.

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Phosphorylation of the Catalytic Subunit of Rat Renal Na+,K+-ATPase by Classical PKC Isoforms

Cited by 31 publications

References 33 publications

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

Protein Kinase C-α and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-induced Apoptosis in Renal Cells

Three Ubiquitination Sites of Organic Anion Transporter-1 Synergistically Mediate Protein Kinase C–Dependent Endocytosis of the Transporter

Lysine 48-Linked Polyubiquitination of Organic Anion Transporter-1 Is Essential for Its Protein Kinase C–Regulated Endocytosis

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