Effect of complete protein 4.1R deficiency on ion transport properties of murine erythrocytes

Rivera, Alicia; Franceschi, Lucia De; Peters, Luanne L.; Gascard, Philippe; Mohandas, Narla; Brugnara, Carlo

doi:10.1152/ajpcell.00436.2005

Cited by 25 publications

(26 citation statements)

References 40 publications

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“…Relevant to our current study, erythrocytes from 4.1R-null mice exhibit hyperactivity of NHE1 compared with erythrocytes from wild type mice [10]. We now show that 4.1R directly binds to NHE1 in vitro and identify the motifs in 4.1R and NHE1 mediating this interaction.…”

Section: Discussionsupporting

confidence: 80%

“…Our previous finding that NHE1 is hyperactive in 4.1R-null mouse erythrocytes [10] suggests a functional interaction between 4.1R and NHE1, In testing this prediction, we now show that this phenotype reveals an actual physical interaction between 4.1R 80 and NHE1. A GST fusion protein encoding the cytoplasmic domain of NHE1 (NHE1cd; aa 501–815) was able to pull down in vitro translated human 4.1R 80 (Figure 1C, lane 1).…”

Section: Resultssupporting

confidence: 62%

“…Additionally, a recent study showed that β-adducin (Add2) null mouse erythrocytes, which adopt a spherocytic shape, lack α-adducin and SLC9A1/NHE1 [8]. Protein 4.1R-null mouse erythrocytes exhibit a dramatic NHE1 phenotype characterized by cell dehydration and high intracellular Na + resulting from hyperactivity of NHE1 [9,10]. This latter observation demonstrates unequivocally a role for 4.1R 80 in modulating NHE1 activity.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of cytoskeletal protein 4.1R interaction with NHE1 (Na+/H+ exchanger isoform 1)

Nunomura

Denker

Barber

et al. 2012

Biochemical Journal

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Na+/H+ exchanger isoform 1 (NHE1) has been reported to be hyperactive in 4.1R-null erythrocytes (Rivera A et al., Am J Physiol Cell Physiol, 291, C880–886, 2006), supporting a functional interaction between NHE1 and 4.1R. Here we demonstrate that 4.1R binds directly to the cytoplasmic domain of NHE1 (NHE1cd) through the interaction of an EED motif in 4.1R FERM (Four.one/Ezrin/Radixin/Moesin) domain with two clusters of basic amino acids, K519R and R556FNKKYVKK, in NHE1cd, previously shown to mediate phosphatidylinositol 4,5-bisphosphate (PIP2) binding (Aharonovitz et al. J. Cell. Biol., 150, 213–224, 2000). The affinity of this interaction (Kd=100–200nM) is reduced in hypertonic and acidic conditions, demonstrating that this interaction is of electrostatic nature. The binding affinity is also reduced upon binding of Ca2+-saturated calmodulin (Ca2+/CaM) to 4.1R FERM domain. We propose that 4.1R regulates NHE1 activity through a direct protein-protein interaction that can be modulated by intracellular pH and Na+ and Ca2+ concentrations.

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Section: Discussionsupporting

confidence: 80%

Section: Resultssupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

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Characterization of cytoskeletal protein 4.1R interaction with NHE1 (Na+/H+ exchanger isoform 1)

Nunomura

Denker

Barber

et al. 2012

Biochemical Journal

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“…The Na-H exchange and K-Cl co-transport might be secondarily activated either by possible abnormal functional interactions between membrane proteins and the transmembrane ion transport pathway or by perturbations in signal transduction pathways modulating ion movements through the membrane, as previously described in mouse red cells genetically lacking band 4.1. 10,29 Since the activity of the membrane cation transport pathways is related to cyclic phosphorylation-dephosphorylation events by kinase phosphatases, we evaluated the membrane tyrosine phosphorylation profile in diseased red cells. In diseased red cells, we observed an increase of band 3 tyrosine phosphorylation, most likely due to increased membrane association of Syk and Lyn kinases which have already been reported to tyrosine-phosphorylate band 3.…”

Section: Discussionmentioning

confidence: 99%

A novel erythroid anion exchange variant (Gly796Arg) of hereditary stomatocytosis associated with dyserythropoiesis

Iolascon¹,

Falco²,

Borgèse³

et al. 2009

Haematologica

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Background \ud \ud Stomatocytoses are a group of inherited autosomal dominant hemolytic anemias and include overhydrated hereditary stomatocytosis, dehydrated hereditary stomatocytosis, hereditary cryohydrocytosis and familial pseudohyperkalemia. \ud \ud Design and Methods \ud \ud We report a novel variant of hereditary stomatocytosis clue to a de novo band 3 mutation (p. G796R-band3 CEINGE) associated with a dyserythropoietic phenotype. Band 3 genomic analysis, measurement at of hematologic parameters and red cell indices and morphological analysis of bone marrow were carried out. We then evaluated the red cell membrane permeability and ion transport systems by functional studies of the patients erythrocytes and Xenopus oocytes transfected with mutated band 3. We analyzed the red cell membrane tyrosine phosphorylation profile and the membrane association of the tyrosine kinases Syk and Lyn from the Src-family-kinase group, since the activity of the membrane cation transport pathways is related to cyclic phosphorylation-dephosphorylation events. \ud \ud Results \ud \ud The patient showed mild hemolytic anemia with circulating stomatocytes together with signs of dyserythropoiesis. Her red cells displayed increased Na(+) content with decreased K(+) content and abnormal membrane cation transport activities. Functional characterization of band 3 CEINGE in Xenopus oocytes showed that the mutated band 3 is converted from being an anion exchanger (Cl(-), HCO(3)(-)) to being a cation pathway for Na(+) and K(+). Increased tyrosine phosphorylation of some red cell membrane proteins was observed in diseased erythrocytes. Syk and Lyn membrane association was increased in the patient's red cells compared to in normal controls, indicating perturbation of phospho-signaling pathways involved in cell volume regulation events. \ud \ud Conclusions \ud \ud Band 3 CEINGE alters function from that of anion exchange to cation transport, affects the membrane tyrosine phosphorylation profile, in particular of band 3 and stomatin, and its presence during red cell development likely contributes to dyserythropiesis

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“…Although this is not a knockout of the entire 4.1R gene, and expression of residual 4.1R has been reported (Stagg et al, 2008), the mice have significant phenotypes. In addition to a predicted hemolytic anemia, the mice have cardiac and kidney defects, neurobehavioral deficits and smaller litter sizes with low survival (Kang et al, 2009;Rivera et al, 2006;Stagg et al, 2008). Examining MEFs from these mice, we observed a number of nuclear deficits resembling those in human cells with depleted 4.1R, including emerin and A-type lamin malfunctions.…”

Section: Introductionmentioning

confidence: 84%

Structural protein 4.1R is integrally involved in nuclear envelope protein localization, centrosome–nucleus association and transcriptional signaling

Meyer

Almendrala

et al. 2011

Journal of Cell Science

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SummaryThe multifunctional structural protein 4.1R is required for assembly and maintenance of functional nuclei but its nuclear roles are unidentified. 4.1R localizes within nuclei, at the nuclear envelope, and in cytoplasm. Here we show that 4.1R, the nuclear envelope protein emerin and the intermediate filament protein lamin A/C co-immunoprecipitate, and that 4.1R-specific depletion in human cells by RNA interference produces nuclear dysmorphology and selective mislocalization of proteins from several nuclear subcompartments. Such 4.1R-deficiency causes emerin to partially redistribute into the cytoplasm, whereas lamin A/C is disorganized at nuclear rims and displaced from nucleoplasmic foci. The nuclear envelope protein MAN1, nuclear pore proteins Tpr and Nup62, and nucleoplasmic proteins NuMA and LAP2 also have aberrant distributions, but lamin B and LAP2 have normal localizations. 4.1R-deficient mouse embryonic fibroblasts show a similar phenotype. We determined the functional effects of 4.1R-deficiency that reflect disruption of the association of 4.1R with emerin and A-type lamin: increased nucleus-centrosome distances, increased -catenin signaling, and relocalization of -catenin from the plasma membrane to the nucleus. Furthermore, emerin-and lamin-A/C-null cells have decreased nuclear 4.1R. Our data provide evidence that 4.1R has important functional interactions with emerin and A-type lamin that impact upon nuclear architecture, centrosome-nuclear envelope association and the regulation of -catenin transcriptional co-activator activity that is dependent on -catenin nuclear export.

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Effect of complete protein 4.1R deficiency on ion transport properties of murine erythrocytes

Cited by 25 publications

References 40 publications

Characterization of cytoskeletal protein 4.1R interaction with NHE1 (Na+/H+ exchanger isoform 1)

Characterization of cytoskeletal protein 4.1R interaction with NHE1 (Na+/H+ exchanger isoform 1)

A novel erythroid anion exchange variant (Gly796Arg) of hereditary stomatocytosis associated with dyserythropoiesis

Structural protein 4.1R is integrally involved in nuclear envelope protein localization, centrosome–nucleus association and transcriptional signaling

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