title: GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2.
abstract: Epithelial Na(+) channels (ENaC) mediate the transport of sodium (Na) across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4 and Nedd4-2, which bind to proline-rich motifs (PY motifs) present in the C-termini of ENaC subunits. Loss of inhibition leads to hypertension. ENaC channels are maintained in the active state by G-protein-coupled receptor kinase 2 (GRK2), an enzyme implicated in the development of essential hypertension. Here, we report that GRK2 interacts not only with ENaC, but also with both Nedd4 and Nedd4-2. Additionally, GRK2 is capable of phosphorylating both Nedd4 and Nedd4-2 at multiple sites. Of possible significance is the phosphorylation of the threonine at position 466 in Nedd4, which is located in the area of the ww3 domain that binds ENaC. These results support and extend the role of GRK2 in sodium transport regulation.
authors.affiliation: Bosch Institute, Department of Pathology, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Angeles
authors.initials: A
authors.lastname: Sanchez-Perez
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
authors.forename: David I
authors.initials: DI
authors.lastname: Cook
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport; D054769:G-Protein-Coupled Receptor Kinase 2; D006801:Humans; D008969:Molecular Sequence Data; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation; D011485:Protein Binding; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2