The role of NHERF‐1 in the regulation of renal proximal tubule sodium–hydrogen exchanger 3 and sodium‐dependent phosphate cotransporter 2a

Department of Medicine, Division of Nephrology, University of Maryland, School of Medicine, 22, South Greene Street, Baltimore, MD 21202, USA.
The Journal of Physiology (Impact Factor: 4.54). 09/2005; 567(Pt 1):27-32. DOI: 10.1113/jphysiol.2005.086777
Source: PubMed

ABSTRACT Adaptor proteins containing PDZ interactive domains have been recently identified to regulate the trafficking and activity of ion transporters and channels in epithelial tissue. In the renal proximal tubule, three PDZ adaptor proteins, namely NHERF-1, NHERF-2 and PDZK1, are expressed in the apical membrane, heterodimerize with one another, and, at least in vitro, are capable of binding to NHE3 and Npt2a, two major regulated renal proximal tubule apical membrane transporters. Studies using NHERF-1 null mice have begun to provide insights into the organization of these adaptor proteins and their specific interactions with NHE3 and Npt2a. Experiments using brush border membranes and cultured renal proximal tubule cells indicate a specific requirement for NHERF-1 for cAMP-mediated phosphorylation and inhibition of NHE3. NHERF-1 null mice demonstrate increased urinary excretion of phosphate associated with mistargeting of Npt2a to the apical membrane of renal proximal tubule cells. NHERF-1 null animals challenged with a low phosphate diet and proximal tubule cells from these animals cultured in a low phosphate media fail to adapt as well as wild-type mice. These studies indicate a unique requirement for NHERF-1 in cAMP regulation of NHE3 and in the trafficking of Npt2a.

Download full-text


Available from: Shirish Shenolikar, Jun 24, 2014
  • Source
    The Journal of Physiology 08/2005; 567(1). DOI:10.1113/jphysiol.2005.089698 · 4.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Phosphate is essential for growth and maintenance of the skeleton and for generating high-energy phosphate compounds. Evolutionary adaptation to high dietary phosphorous in humans and other terrestrial vertebrates involves regulated mechanisms assuring the efficient renal elimination of excess phosphate. These mechanisms prominently include PTH, FGF23, and Vitamin D, which directly and indirectly regulate phosphate transport. Disordered phosphate homeostasis is associated with pathologies ranging from kidney stones to kidney failure. Chronic kidney disease results in hyperphosphatemia, an elevated calcium×phosphate product with considerable morbidity and mortality, mostly associated with adverse cardiovascular events. This chapter highlights recent findings and insights regarding the hormonal regulation of renal phosphate transport along with imbalances of phosphate balance due to acquired or inherited diseases states. © 2015 Elsevier Inc. All rights reserved.
    Vitamins & Hormones 01/2015; 98:249-306. DOI:10.1016/bs.vh.2015.01.002 · 1.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The regulation of the cell cycle by the ubiquitin-proteasome system is dependent on the activity of E3 ligases. Skp2 (S-phase kinase associated protein-2) is the substrate recognition subunit of the E3 ligase that ubiquitylates the cell cycle inhibitors p21cip1 and p27kip1 thus promoting cell cycle progression. Increased expression of Skp2 is frequently observed in diseases characterized by excessive cell proliferation, such as cancer and neointima hyperplasia. The stability and cellular localization of Skp2 are regulated by Akt, but the molecular mechanisms underlying these effects remain only partly understood. The scaffolding protein Ezrin-Binding Phosphoprotein of 50 KDa (EBP50) contains two PDZ domains and plays a critical role in the development of neointimal hyperplasia. Here we report that EBP50 directly binds Skp2 via its first PDZ domain. Moreover, EBP50 is phosphorylated by Akt on T156 within the second PDZ domain, an event that allosterically promotes binding to Skp2. The interaction with EBP50 causes cytoplasmic localization of Skp2, increases Skp2 stability and promotes proliferation of primary vascular smooth muscle cells. Collectively, these studies define a novel regulatory mechanism contributing to aberrant cell growth and highlight the importance of scaffolding function of EBP50 in Akt-dependent cell proliferation. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 12/2014; 290(5). DOI:10.1074/jbc.M114.609768 · 4.60 Impact Factor