Ezrin-anchored Protein Kinase A Coordinates Phosphorylation-dependent Disassembly of a NHERF1 Ternary Complex to Regulate Hormone-sensitive Phosphate Transport

Abstract

Background: Some inherited defects in NHERF1 are associated with high phosphate (P i ) excretion and skeletal abnormalities. Results: NHERF1 forms a multiprotein complex with Npt2a and ezrin. Mutants fail to assemble this ternary complex. Conclusion:The NHERF1 ternary complex is required for PTH-sensitive P i transport. Significance: NHERF1 mutations may cause disease processes through structural changes that prevent assembly of multiprotein complexes.

Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) Directly Regulates Osteogenesis

“…Renal phosphate excretion increased in NHERF1-null mice ( Fig. 2C), in keeping with published work (11), consistent with NHERF1 regulating sodium phosphate cotransporter 2a membrane retention and phosphate reabsorption (23). We further found that urinary cAMP excretion, a reflection of the phosphaturic action of PTH, also increased in NHERF1-null mice (Fig.…”

Phosphorylation of Ezrin-Radixin-Moesin-binding Phosphoprotein 50 (EBP50) by Akt Promotes Stability and Mitogenic Function of S-phase Kinase-associated Protein-2 (Skp2)

“…These data suggest that phosphorylation of Thr-156 exerts an allosteric effect on PDZ1, leading to increased affinity for Skp2. Consistent with this model is the observation that a human mutation in the Akt consensus motif of EBP50 (R153Q) significantly decreases the interaction with the sodium/phosphate transporter Npt2a which, like Skp2, binds exclusively to PDZ1 (25).…”

“…Plasmids and Mutagenesis-The plasmid encoding N-terminal Flag-human EBP50 was described previously (25). The mutants S1, S2, ⌬ERM, S1/S2, and T156A EBP50 constructs were made from Flag-EBP50 by using the QuikChange sitedirected mutagenesis kit from Stratagene (La Jolla, CA).…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…Dimerization is thought to be mediated either by intermolecular interactions between PDZ domains or by an intramolecular head-totail interaction between the carboxy terminus and a PDZ domain within the same protein, as is the case with NHERF1 (Lau and Hall, 2001;Morales et al, 2007). Head-to-tail dimerization of NHERF1 is mediated by the interaction between the carboxy terminus, which itself serves as a PDZ-ligand (-FSNL), with PDZ2 (Morales et al, 2007;Wang et al, 2012). Although the biologic significance of NHERF dimerization is not fully appreciated, a recent study showed that heterodimerization of NHERF2 and NHERF3 is required for the inhibition of Na + /H + exchanger-3 by carbachol (Yang et al, 2014).…”

“…Individual PDZ proteins may contain multiple PDZ domains as well as other interaction modules such as ezrin-binding domains (EBDs). PDZ proteins lack intrinsic catalytic activity and therefore function primarily as scaffold proteins, where they execute a range of biologic functions that include establishing and maintaining cellular polarity, assembling multiprotein signaling complexes, and anchoring transmembrane proteins, including transporters, to the actin cytoskeleton via interactions with the ERM family of adapters (Ponting et al, 1997;Wang et al, 2007Wang et al, , 2010Wang et al, , 2012Georgescu et al, 2014;Zheng et al, 2014).…”