Kidney kinase network regulates renal ion cotransport

Abstract

Protein kinases catalyze the phosphorylation of serine/threonine or tyrosine residues, which may directly alter a protein's functional properties. Kinases can also regulate protein functions indirectly, for example, by controlling the composition and/or subcellular localization of members of multiprotein complexes that associate with the regulated protein. In this issue of the JCI, two separate studies by Weinman et al. and Yang et al. examine the second of these two modes of kinase-mediated regulation and demonstrate the effects of kinases on two Na(+)-driven renal cotransporters (see the related articles beginning on pages 3403 and 3412). Their results reveal important implications for phosphate and salt homeostasis, respectively.

Figure 1. Kinase signaling networks regulating ion transport in the kidney.

Left: Regulation of the PT cell Na⁺-P_i cotransporter Npt2a by PTH, via apical and basolateral PTH receptors. As reported in this issue by Weinman et al. (1), phosphorylation at Ser77 of NHERF-1 results in a dissociation of Npt2a from NHERF-1, consequent Npt2a internalization, and an increased excretion of phosphate in the urine. Right: DCT cells express the Na⁺-Cl^– cotransporter NCC, which is inhibited by thiazides. The study by Yang et al. (2) in this issue of the JCI reports that WNK3, a member of the WNK kinase family, interacts with WNK1 and WNK4 to regulate the phosphorylation and activity of NCC. WNK kinases are regulated by stimuli such as changes in aldosterone or extracellular potassium levels. Dotted arrows indicate that the nature of interaction between kinases (direct or indirect) is not known to date. KS-WNK1, kidney-specific WNK1.