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Effects of PHAII mutations in WNK signaling molecules on the signaling In normal states, CUL3, KLHL3, and WNK1/4 form the E3 ubiquitin ligase complex to regulate WNK1/4 degradation by the ubiquitin-proteasome system (left: normal); in PHAII, mutations in each intermolecular binding site fail this complex formation, subsequently, accumulation of WNK1/4 leads to activation of downstream OSR1/SPAK-NCC signaling.
