Ranbpm Likely Mediates Sodium Chloride Cotransporter (Ncc) Regulation Through A Wnk4-Erk 1/2 Signaling Pathway

Ran‐Binding protein M (RanBPM) is a nucleoplasmic protein. A recent study has shown that RanBPM is an inhibitor of ERK 1/2 signaling pathway by regulating c‐Raf stability. WNK is a serine/threonine kinase. Mutations in WNK1 and WNK4 cause pseudohypoaldosteronism type II (PHA II), characterized by hypertension, hyperkalemia and metabolic acidosis. Our previous study has shown that WNK4 inhibits NCC by activating ERK 1/2 signaling pathway. To determine whether WNK4 inhibits NCC through RanBPM‐dependent ERK 1/2 signaling pathway, we first investigated interaction between WNK4 and RanBPM using yeast‐two hybrid screening technique. We found that WNK4 interacted with RanBPM. RanBPM was also shown to prevent ERK 1/2 phosphorylation in response to EGF stimulation. When mouse distal convoluted cells (mDCT) were transfected with myc‐RanBPM, ERK 1/2 phosphorylation was decreased while NCC protein expression increased. When mDCT cells were transfected with siRNA RanBPM, ERK 1/2 phosphorylation was increased. These data suggest that 1) WNK4 interacts with RanBPM which is an inhibitor of ERK 1/2 phosphorylation; 2) RanBPM mediates NCC regulation likely through ERK1/2 signaling pathway.