Localization and interaction of NHERF isoforms in the renal proximal tubule of the mouse

Wade, James B.; Liu, Jie; Coleman, Richard A.; Cunningham, Rochelle; Steplock, Deborah; Lee-Kwon, Whaseon; Pallone, Thomas L.; Shenolikar, Shirish; Weinman, Edward J.

doi:10.1152/ajpcell.00092.2003

Cited by 99 publications

(112 citation statements)

References 32 publications

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“…However, they retain megalin/ ClC-5-and NHE3-dependent albumin uptake pathways (36,50), and NHE3 is reported to traffic from the microvilli to the intravillar regions (34). Importantly, the distribution of NHERF1 in the microvilli domain and NHERF2 in regions between the microvilli that we report corresponds to their distributions in the mouse and human proximal tubules (29,31), thus OK cells are a suitable model for the investigation of the molecular basis of receptor-mediated albumin uptake (see Ref. 2).…”

Section: Discussionsupporting

confidence: 62%

“…NHERF proteins clearly have the capacity to nucleate the formation of functional complexes at the plasma membrane (30,32) and restrict the mobility of plasma membrane proteins, such as NHE3 (33,34). Thus the organized subcellular distribution of NHERF1/2 is speculated to play a role in the specific interactions that mediate the physiological regulation of transporter function (31). The current study was therefore undertaken to investigate the potential involvement of NHERF1/2 in albumin uptake and whether this involved interactions with ClC-5, a key component of the albumin endocytic complex.…”

mentioning

confidence: 99%

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Regulation of Albumin Endocytosis by PSD95/Dlg/ZO-1 (PDZ) Scaffolds

Hryciw

Ekberg

Ferguson

et al. 2006

Journal of Biological Chemistry

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The constitutive reuptake of albumin from the glomerular filtrate by receptor-mediated endocytosis is a key function of the renal proximal tubules. Both the Cl ؊ channel ClC-5 and the Na ؉ -H ؉ exchanger isoform 3 are critical components of the macromolecular endocytic complex that is required for albumin uptake, and therefore the cell-surface levels of these proteins may limit albumin endocytosis. This study was undertaken to investigate the potential roles of the epithelial PDZ scaffolds, Na ؉ -H ؉ exchange regulatory factors, NHERF1 and NHERF2, in albumin uptake by opossum kidney (OK) cells. We found that ClC-5 co-immunoprecipitates with NHERF2 but not NHERF1 from OK cell lysate. Experiments using fusion proteins demonstrated that this was a direct interaction between an internal binding site in the C terminus of ClC-5 and the PDZ2 module of NHERF2. In OK cells, NHERF2 is restricted to the intravillar region while NHERF1 is located in the microvilli. Silencing NHERF2 reduced both cell-surface levels of ClC-5 and albumin uptake. Conversely, silencing NHERF1 increased cell-surface levels of ClC-5 and albumin uptake, presumably by increasing the mobility of NHE3 in the membrane and its availability to the albumin uptake complex. Surface biotinylation experiments revealed that both NHERF1 and NHERF2 were associated with the plasma membrane and that NHERF2 was recruited to the membrane in the presence of albumin. The importance of the interaction between NHERF2 and the cytoskeleton was demonstrated by a significant reduction in albumin uptake in cells overexpressing an ezrin binding-deficient mutant of NHERF2. Thus NHERF1 and NHERF2 differentially regulate albumin uptake by mechanisms that ultimately alter the cell-surface levels of ClC-5.

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Section: Discussionsupporting

confidence: 62%

mentioning

confidence: 99%

Regulation of Albumin Endocytosis by PSD95/Dlg/ZO-1 (PDZ) Scaffolds

Hryciw

Ekberg

Ferguson

et al. 2006

Journal of Biological Chemistry

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“…Importantly, although NHERF-1 and NHERF-2 were originally described in the kidney, Northern blot analysis shows an overlapping and wide-spread distribution pattern for NHERF-1 and NHERF-2 mRNAs in human tissues, including brain, heart, colon, small intestine, liver, prostate, spleen, and placenta (Weinman et al 1995;Yun et al 1997). Immunohistochemical studies have demonstrated NHERF-1 and NHERF-2 in the human (Weinman et al 2002) and mouse (Wade et al 2003) kidney, NHERF-1 in the mouse retina (Nawrot et al 2004) and Schwann cell processes (Gatto et al 2003), and NHERF-2 in endothelia and pericytes from rat descending vasa recta (Lee-Kwon et al 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, its close relative NHERF-2 (also called E3KARP) was cloned and characterized (Yun et al 1997). NHERF-1 and NHERF-2 consist of 358 and 337 amino acids, respectively, sharing 54% homology and possess two PDZ domains and a C-terminal ezrin-radixin-moesinmerlin (ERM)-binding domain that can interact with the actin cytoskeleton (Fanning and Anderson 1999;Shenolikar and Weinman 2001;Wade et al 2003;Yun 2003;Shenolikar et al 2004). NHERF-1 and NHERF-2 bind PDZ motifs in the C-termini of target proteins to assemble signaling/transport complexes at the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

Postnatal developmental expression of the PDZ scaffolds Na+-H+ exchanger regulatory factors 1 and 2 in the rat cochlea

et al. 2005

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Sensory transduction in the mammalian cochlea requires the maintenance of specialized fluid compartments with distinct ionic compositions. This is achieved by the concerted action of diverse ion channels and transporters, some of which can interact with the PDZ scaffolds, Na + -H + exchanger regulatory factors 1 and 2 (NHERF-1, NHERF-2). Here, we report that NHERF-1 and NHERF-2 are widely expressed in the rat cochlea, and that their expression is developmentally regulated. Reverse transcription/polymerase chain reaction (RT-PCR) and Western blotting initially confirmed the RNA and protein expression of NHERFs. We then performed immunohistochemistry on cochlea during various stages of postnatal development. Prior to the onset of hearing (P8), NHERF-1 immunolabeling was prominently polarized to the apical membrane of cells lining the endolymphatic compartment, including the stereocilia and cuticular plates of the inner and outer hair cells, marginal cells of the stria vascularis, Reissner's epithelia, and tectorial membrane. With maturation (P21, P70), NHERF-1 immunolabeling was reduced in the above structures, whereas labeling increased in the apical membrane of the interdental cells of the spiral limbus and the inner and outer sulcus cells, Hensen's cells, the inner and outer pillar cells, Deiters cells, the inner border cells, spiral ligament fibrocytes, and spiral ganglion neurons (particularly type II). NHERF-1 expression in strial basal and intermediate cells was persistent. NHERF-2 immunolabeling was similar to that for NHERF-1 during postnatal development, with the exception of expression in the synaptic regions beneath the outer hair cells. NHERF-1 and NHERF-2 co-localized with glial fibrillary acidic protein and vimentin in glia. The cochlear localization of NHERF scaffolds suggests that they play important roles in the developmental regulation of ion transport, homeostasis, and auditory neurotransmission.

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“…For example, it is well known that NaPi-2a is integrated in a series of macromolecular complexes whose architecture is based on PDZ (PSD-95, discs-large, and ZO-1) protein interactions (12)(13)(14)(15)(16)(17)(18)(19). NaPi-2a participates in this complex by means of a class I PDZ-binding site located at its C terminus, comprising its last three amino acids (TRL).…”

mentioning

confidence: 99%

Role of PDZK1 Protein in Apical Membrane Expression of Renal Sodium-coupled Phosphate Transporters

Giral

Lanzanò

Caldas

et al. 2011

Journal of Biological Chemistry

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The sodium-dependent phosphate (Na/P i ) transporters NaPi-2a and NaPi-2c play a major role in the renal reabsorption of P i . The functional need for several transporters accomplishing the same role is still not clear. However, the fact that these transporters show differential regulation under dietary and hormonal stimuli suggests different roles in P i reabsorption. The pathways controlling this differential regulation are still unknown, but one of the candidates involved is the NHERF family of scaffolding PDZ proteins. We propose that differences in the molecular interaction with PDZ proteins are related with the differential adaptation of Na/P i transporters. Pdzk1 ؊/؊ mice adapted to chronic low P i diets showed an increased expression of NaPi-2a protein in the apical membrane of proximal tubules but impaired up-regulation of NaPi-2c. These results suggest an important role for PDZK1 in the stabilization of NaPi-2c in the apical membrane. We studied the specific protein-protein interactions of Na/P i transporters with NHERF-1 and PDZK1 by FRET. FRET measurements showed a much stronger interaction of NHERF-1 with NaPi-2a than with NaPi-2c. However, both Na/P i transporters showed similar FRET efficiencies with PDZK1. Interestingly, in cells adapted to low P i concentrations, there were increases in NaPi-2c/PDZK1 and NaPi-2a/NHERF-1 interactions. The differential affinity of the Na/P i transporters for NHERF-1 and PDZK1 proteins could partially explain their differential regulation and/or stability in the apical membrane. In this regard, direct interaction between NaPi-2c and PDZK1 seems to play an important role in the physiological regulation of NaPi-2c.The type II sodium-coupled phosphate (Na/P i ) 3 transporters are the molecules responsible for tubular reabsorption of P i and are the target of hormonal and nonhormonal mechanisms that control phosphate homeostasis. NaPi-2a (NaPiIIa) is responsible for ϳ70% of the P i reabsorbed in the adult kidney of mice, whereas NaPi-2c (NaPiIIc) handles the remaining 30% (1, 2). A low dietary P i intake induces an increase of P i reabsorption in the proximal tubule mediated by augmented apical expression of NaPi-2a and NaPi-2c transporters and consequent increased P i uptake (3-6).Despite sharing a very similar molecular structure, NaPi-2a and NaPi-2c exhibit an increasing list of physiological differences. For example, whereas NaPi-2a is electrogenic, NaPi-2c is electroneutral (4, 7). In addition, both transporters participate in the renal adaptation to changes in dietary P i with different characteristics. In response to a high P i intake, NaPi-2a abundance decreases quickly (less than 1 h), internalization takes place in a microtubule-independent way, and molecules are targeted to the lysosomes via endosomes (8, 9). In contrast, under a high P i intake, NaPi-2c abundance decreases slowly (4 h), molecules are internalized through a microtubule-dependent pathway, and rather than being degraded, they are accumulated in a subapical compartment (10). Similar differences...

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Localization and interaction of NHERF isoforms in the renal proximal tubule of the mouse

Cited by 99 publications

References 32 publications

Regulation of Albumin Endocytosis by PSD95/Dlg/ZO-1 (PDZ) Scaffolds

Regulation of Albumin Endocytosis by PSD95/Dlg/ZO-1 (PDZ) Scaffolds

Postnatal developmental expression of the PDZ scaffolds Na+-H+ exchanger regulatory factors 1 and 2 in the rat cochlea

Role of PDZK1 Protein in Apical Membrane Expression of Renal Sodium-coupled Phosphate Transporters

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