New roles of the Na+/H+ exchange regulatory factor 1 scaffolding protein: a review

摘要

Cellular information is transmitted through coordinated signaling networks that rely heavily on scaffolding proteins, which enable proper transmission of cellular information by organizing multiprotein complexes. Na+/H+ exchange regulatory factor 1 [NHERF1; ezrin-binding protein-50 (EBP50)], is a member of the postsynaptic density protein 95IDrosopliila disc large tumor suppressor/zonula occulens-1 (PSD-95/DIg/ ZO-1) homology (PDZ) family, initially identified (58) as scaffolds for the formation and localization of protein complexes composed of hormone receptors, signal transduction pathway components, transporters, and channels on the apical membrane of epithelial cells (11, 29). NHERF1 has two tandem PDZ domains that exhibit domain-specific binding properties, a carboxy-terminal ezrin-binding domain, which enables the localization of these protein complexes to the plasma membrane through interaction with the ezrin-radixin-moesin (ERM) family of membrane-targeting proteins, and a cholesterol recognition/interaction amino acid consensus domain,whose function has not been well defined for NHERF1 but is thought to regulate membrane association (13). Regulation of NHE3 function by parathyroid hormone (PTH), apical membrane anchoring and regulation of Na+-dependent phosphate transporter 2a (Npt2a) expression by PTH and dopamine, and regulation of the Na+-K+-ATPase are examples of how NHERFl's protein complex scaffolding and localization capabilities in the kidney facilitate the efficient regulation of ion transport. Studies within the past decade, however, have uncovered NHERF1 involvement in a variety of functions across multiple cell types, includings cell structure and trafficking, tumorigenesis and tumor behavior (12, 19), inflammatory responses (2, 18), and tissue injury (8, 32, 33). Divergent and contradictory effects of NHERF1 have been reported, making it difficult to predict how differences in expression, localization, or phosphorylation of NHERF1 will affect a specific cell function. The purpose of this review is to highlight this newer information and speculate on the implications for renal physiology and pathophysiology.