Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

• DOI: 10.1073/pnas.1418342111
• Publication Date: 2014-10-14T04:00:15Z
• Authors: Shigeru Shibata; Juan Pablo Arroyo; María Castañeda-B...; Jeremy Puthumana; Junhui Zhang; Shunya Uchida; Kathryn L. Stone; TuKiet T. Lam; Richard P. Lifton
• Keywords: 0301 basic medicine; Angiotensin II; Microfilament Proteins; Molecular Sequence Data; Protein Serine-Threonine Kinases; Kidney; Cell Line; 3. Good health; Mice, Inbred C57BL; Phosphoserine; 03 medical and health sciences; Proteolysis; Animals; Humans; Amino Acid Sequence; Phosphorylation; Carrier Proteins; Protein Kinase C; Adaptor Proteins, Signal Transducing; Protein Binding; Signal Transduction

Significance Aldosterone produces distinct adaptive responses in volume depletion and hyperkalemia. Mutations with-no-lysine (WNK) kinases or ubiquitin ligases containing Cullin 3 (CUL3) Kelch-like (KLHL3) cause a Mendelian disease featuring hypertension hyperkalemia due to constitutive renal salt reabsorption inhibited K + secretion. WNKs modulate activities of aldosterone-regulated electrolyte flux pathways, WNK levels are regulated by CUL3/KLHL3; disease-causing mutations prevent degradation. This manuscript shows that angiotensin II (AII), hormone produced only depletion, induces PKC-mediated phosphorylation KLHL3, preventing degradation phenocopying KLHL3 mutations. These findings provide mechanism which AII signaling alters WNK4, promoting increased reduced