RGD Reference Report - Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform. - Rat Genome Database

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Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform.

Authors: Subramanya, AR  Yang, CL  Zhu, X  Ellison, DH 
Citation: Subramanya AR, etal., Am J Physiol Renal Physiol. 2006 Mar;290(3):F619-24. Epub 2005 Oct 4.
RGD ID: 11535105
Pubmed: (View Article at PubMed) PMID:16204408
DOI: Full-text: DOI:10.1152/ajprenal.00280.2005

With-no-lysine kinase-1 (WNK1) gene mutations cause familial hyperkalemic hypertension (FHHt), a Mendelian disorder of excessive renal Na+ and K+ retention. Through its catalytic activity, full-length kinase-sufficient WNK1 (L-WNK1) suppresses its paralog, WNK4, thereby upregulating thiazide-sensitive Na-Cl cotransporter (NCC) activity. The predominant renal WNK1 isoform, KS-WNK1, expressed exclusively and at high levels in distal nephron, is a shorter kinase-defective product; the function of KS-WNK1 must therefore be kinase independent. Here, we report a novel role for KS-WNK1 as a dominant-negative regulator of L-WNK1. Na+ transport studies in Xenopus laevis oocytes demonstrate that KS-WNK1 downregulates NCC activity indirectly, by inhibiting L-WNK1. KS-WNK1 also associates with L-WNK1 in protein complexes in oocytes and attenuates L-WNK1 kinase activity in vitro. These observations suggest that KS-WNK1 plays an essential role in the renal molecular switch regulating Na+ and K+ balance; they provide insight into the kidney-specific phenotype of FHHt.

Annotation

Gene Ontology Annotations    

Biological Process

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Wnk1  (WNK lysine deficient protein kinase 1)
Wnk4  (WNK lysine deficient protein kinase 4)


Additional Information