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Protein kinase C regulates organic anion transporter 1 through phosphorylating ubiquitin ligase Nedd4-2

Zhou Yu1, Chenchang Liu1, Jinghui Zhang1

  • 1Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.

BMC Molecular and Cell Biology
|October 19, 2021
PubMed
Abstract

Insights

Protein kinase C (PKC) regulates the drug transporter OAT1 by phosphorylating Nedd4-2. This phosphorylation reduces OAT1 cell surface expression and transport activity, impacting drug disposition.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • Organic anion transporter 1 (OAT1) is crucial for renal drug disposition.
  • Protein kinase C (PKC) activation reduces OAT1 surface expression and function.
  • Nedd4-2 ubiquitin ligase mediates OAT1 internalization, but its direct regulation by PKC is unclear.

Purpose of the Study:

  • To investigate the role of Nedd4-2 phosphorylation in PKC-mediated OAT1 regulation.
  • To determine if Nedd4-2 is a direct substrate for PKC.

Main Methods:

  • Investigated Nedd4-2 phosphorylation in response to PKC activation.
  • Assessed OAT1 ubiquitination, cell surface expression, and transport activity.
  • Utilized PKC-specific inhibitors and a quadruple mutant of Nedd4-2.

Main Results:

  • PKC activation increased Nedd4-2 phosphorylation and OAT1 ubiquitination.
  • This led to decreased OAT1 cell surface expression and transport function.
  • A quadruple Nedd4-2 mutant partially inhibited PKC's effects.

Conclusions:

  • PKC directly phosphorylates Nedd4-2, regulating OAT1.
  • Four specific phosphorylation sites on Nedd4-2 are critical for this regulation.
Keywords:
Drug transporterNedd4–2Organic anion transporter 1PhosphorylationProtein kinase CRegulationUbiquitination

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