Coming out of the NHERF family

Abstract

In this issue of The Journal of Physiology, four individual reviews are presented that together made up a symposium entitled, ‘PDZ Domain Scaffolding Proteins and their Functions in Polarized Cells’, presented in San Diego, CA, USA on 4 April 2005 (Donowitz et al. 2005; Hernando et al. 2005; Thelin et al. 2005; Weinman et al. 2005). All presentations dealt with four multi PDZ domain containing proteins that are present in the brush border of mammalian small intestine, colon and renal proximal tubule. These proteins have between two and four PDZ domains each, and while all occur in epithelial cell brush borders, they have a widely divergent organ, cell and membrane, as well as species expression. The four proteins were cloned separately by multiple groups of scientists and consequently have multiple names, the most widely used of each being NHERF (Na/H exchanger regulatory factor), E3KARP (NHE3 kinase A regulatory protein), PDZK1 (PDZ domain protein from kidney 1) and IKEPP (intestinal and kidney epithelial PDZ domain protein). The authors of these symposium reviews include several of those who were responsible for cloning each of the four NHERF family members. As was reported at this meeting, these four proteins are all closely related. This relationship was determined from BLAST searches which demonstrated that the most closely homologous mammalian proteins for each of these proteins were the other three members of this family (Donowitz et al. 2005). Eleven of the twelve total PDZ domains present in these four proteins could be divided into three groups based on having high identity with a threshold of 20% (Donowitz et al. 2005; Thelin et al. 2005). Each of the 12 PDZ domains could have its origin traced to the same two PDZ domain containing proteins in C. elegans and/or either of two PDZ domain containing proteins in D. melanogaster (Donowitz et al. 2005). Thus we concluded that these four proteins are members of the same gene family. The original names of the first two cloned members of this family, NHERF and E3KARP, were meant to recognize the interactions of these proteins with the brush border Na/H exchanger isoform 3. However, since then ∼60 additional binding substrates of NHERF1 and NHERF2 have been recognized, with the number rapidly increasing and likely to be much larger. Nonetheless, given the widespread use of the NHERF nomenclature in the literature we suggest naming each protein as a member of the NHERF gene family. Moreover, we proposed that they be named to recognize this association in the order of their cloning, rather than using their many current designations, which are shown in parentheses: NHERF1 (NHERF, EBP50) (Donowitz et al. 2005; Hernando et al. 2005; Thelin et al. 2005; Weinman et al. 2005), NHERF2 (E3KARP, TKY-1, SIP-1) (Donowitz et al. 2005; Hernando et al. 2005; Thelin et al. 2005; Weinman et al. 2005), NHERF3 (PDZK1, CLAMP, CAP70, DIPHOR-1, NaPi-CaP1) (Donowitz et al. 2005; Thelin et al. 2005; Weinman et al. 2005) NHERF4 (IKEPP, DIPHOR-2, NaPiCaP2) (Donowitz et al. 2005; Hernando et al. 2005; Thelin et al. 2005; Weinman et al. 2005). A common name is proposed to allow recognition of their relationships in their primary structures and their similar expression pattern in many cell types. Given these similarities, scientists need to establish the specificity of effects attributed to one protein and to show that effects are not compensated by the presence of other NHERF family proteins. Moreover, more than one may be involved in any given regulatory process given their propensity to homo or heteromultimerize with each other. The symposium reviewed progress in understanding the functions of each of the four NHERF family members, with some emphasis on their roles in regulation of NHE3 and NaPiIIa activity, their ligands which have been studied in most detail. Given the importance of their many other ligands, an understanding of the role of this family of proteins is just beginning to be attained and these four reviews should be considered as early progress reports.