Role of NHERF and scaffolding proteins in proximal tubule transport

Division of Nephrology, Department of Medicine, University of Maryland, School of Medicine, Room N3W143, UHM, 22 South Greene Street, Baltimore, MD 21201, USA.
Urological Research (Impact Factor: 1.39). 08/2010; 38(4):257-62. DOI: 10.1007/s00240-010-0294-1
Source: PubMed


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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    • "MAP17 has been found to bind NHeRF1 and NHeRF3 (PDZK1) through its PDZ-binding motif (Pribanic et al., 2003; Silver et al., 2003; Lanaspa et al., 2007). NHeRFs are scaffolding protein defined by the presence of globular PDZ domains that assemble several proteins into functional complexes (Shenolikar et al., 2004; Cunningham et al., 2010; Claperon et al., 2011). The NHeRF proteins regulate cell surface expression and functional activity of transporters (Shenolikar et al., 2004; Lee et al., 2007). "
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