Role of NHERF and scaffolding proteins in proximal tubule transport
ABSTRACT Eukaryotic cells coordinate specific responses to hormones and growth factors by spatial and temporal organization of "signaling components." Through the formation of multiprotein complexes, cells are able to generate "signaling components" that transduce hormone signals through proteins, such as PSD-95/Dlg/ZO-1(PDZ)-containing proteins that associate by stable and dynamic interactions. The PDZ homology domain is a common protein interaction domain in eukaryotes and with greater than 500 PDZ domains identified, it is the most abundant protein interaction domain in eukaryotic cells. The NHERF (sodium hydrogen exchanger regulatory factor) proteins are PDZ domain-containing proteins that play an important role in maintaining and regulating cell function. NHERF-1 was initially identified as a brush border membrane-associated phosphoprotein essential for the cAMP/PKA-induced inhibition of the sodium hydrogen exchanger isoform 3 (NHE3). Mouse, rabbit and human renal proximal tubules also express NHERF-2 (E3KARP), a structurally related protein, which in model cell systems also binds NHE3 and mediates its inhibition by cAMP. PDZK1 (NHERF-3) and IKEPP (NHERF-4) were later identified and found to have similar homology domains, leading to their recent reclassification. Although studies have revealed similar binding partners and overlapping functions for the NHERF proteins, it is clear that there is a significant amount of specificity between them. This review focuses primarily on NHERF-1, as the prototypical PDZ protein and will give a brief summary of its role in phosphate transport and the development of some forms of nephrolithiasis.
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ABSTRACT: Many G protein-coupled receptors (GPCR) exert patterns of cell-specific signaling and function. Mounting evidence now supports the view that cytoplasmic adapter proteins contribute critically to this behavior. Adapter proteins recognize highly conserved motifs such as those for Src homology 3 (SH3), phosphotyrosine-binding (PTB), and postsynaptic density 95/discs-large/zona occludens (PDZ) docking sequences in candidate GPCRs. Here we review the behavior of the Na+/H+ exchange regulatory factor (NHERF) family of PDZ adapter proteins on GPCR signalling, trafficking, and function. Structural determinants of NHERF proteins that allow them to recognize targeted GPCRs are considered. NHERF1 and NHERF2 are capable also of modifying the assembled complex of accessory proteins such as β-arrestins, which have been implicated in regulating GPCR signaling. In addition, NHERF1 and NHERF2 modulate GPCR signaling by altering the G protein to which the receptor binds or affect other regulatory proteins that affect GTPase activity, protein kinase A, phospholipase C, or modify downstream signaling events. Small molecules targeting the site of NHERF1-GPCR interaction are being developed and may become important and selective drug candidates.Pharmacological reviews 08/2011; 63(4):882-900. DOI:10.1124/pr.110.004176 · 18.55 Impact Factor
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ABSTRACT: Regulation of phosphate homeostasis is critical for many biological processes, and both hypophosphatemia and hyperphosphatemia can have adverse clinical consequences. Only a very small percentage (1%) of total body phosphate is present in the extracellular fluid, which is measured by routine laboratory assays and does not reflect total body phosphate stores. Phosphate is absorbed from the gastrointestinal tract via the transcellular route [sodium phosphate cotransporter 2b (NaPi2b)] and across the paracellular pathway. Approximately 85% of the filtered phosphate is reabsorbed from the kidney, predominantly in the proximal tubule, by NaPi2a and NaPi2c, which are present on the brush border membrane. Renal phosphate transport is tightly regulated. Dietary phosphate intake, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D3, and fibroblast growth factor 23 (FGF23) are the principal regulators of phosphate reabsorption from the kidney. Recent advances in genetic techniques and animal models have identified many genetic disorders of phosphate homeostasis. Mutations in NaPi2a and NaPi2c; and hormonal dysregulation of PTH, FGF23, and Klotho, are primarily responsible for most genetic disorders of phosphate transport. The main focus of this educational review article is to discuss the genetic and clinical features of phosphate regulation disorders and provide understanding and treatment options.Pediatric Nephrology 02/2012; 27(9):1477-87. DOI:10.1007/s00467-012-2103-2 · 2.88 Impact Factor
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ABSTRACT: Reactive oxygen species, ROS, are beneficially involved in many signaling pathways that control development and maintain cellular homeostasis. In physiological conditions, a tightly regulated redox balance protects cells from injurious ROS activity, but if the balance is altered, it promotes various pathological conditions including cancer. Understanding the duality of ROS as cytotoxic molecules and key mediators in signaling cascades may provide novel opportunities for improved cancer therapy. MAP17 is a small 17-kDa non-glycosylated membrane protein that is overexpressed in many tumors of different origins, including carcinomas. Immunohistochemical analysis of MAP17 during cancer progression demonstrates that overexpression of the protein strongly correlates with the progression of most types of tumor. Tumor cells that overexpress MAP17 show an increased tumoral phenotype associated with an increase in ROS. However, in non-tumor cells MAP17 increases ROS, resulting in senescence or apoptosis. Therefore, in tumor cells, MAP17 could be a marker for increased oxidative stress and could define new therapeutic approaches. Here, we review the role of MAP17 as a putative oncogene, as well as its role in cancer and anticancer therapies.Biochimica et Biophysica Acta 03/2012; 1826(1):44-52. DOI:10.1016/j.bbcan.2012.03.004 · 4.66 Impact Factor