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PubMed2004

Loss of cooperative function of transforming growth factor-beta signaling proteins, smad3 with embryonic liver fodrin, a beta-spectrin, in primary biliary cirrhosis.

UNLABELLED: Modulation of fibrogenesis, epithelial, and mesenchymal cell fates are prominent effects of transforming growth factor-beta (TGF-beta) signaling by Smad proteins. We have previously shown that Smad2 and Smad3 insufficiency leads to a loss of bile ducts. In addition, Smad3/4 activity is mediated by embryonic liver fodrin (ELF), a beta-Spectrin. In mouse elf(-/-) mutants and in liver explant cultures, loss of ELF function results in T lymphocytic proliferation and absent intrahepatic bile ducts. A similar phenotype is seen in a number of cholestatic diseases with progressive loss of intrahepatic bile ducts and fibrosis. However, the expression patterns of Smads or role of ELF in cholestatic and fibrotic liver diseases are not yet known. METHODS/RESULTS: We investigated the role of ELF in primary biliary cirrhosis (PBC), autoimmune hepatitis C, chronic viral hepatitis and in livers from mice deficient in Smad2/Smad3. We generated elf(+/-) mutant mice and analyzed for chronic liver disease and hepatocellular cancer (HCC) from 6 to 12 months. Perturbations in ELF expression were consistently seen only in PBC tissues. ELF expression was similarly aberrant in tissues from Smad2(+/-)/Smad3(+/-) mutant mice. Further studies indicated that ELF mislocalization is correlated with aberrant localization of Smad3 in some PBC tissues. Thirteen of 17 elf(+/-) mutant mice developed steatosis, fibrosis, hepatic dysplasia, with HCC in two mice. CONCLUSIONS: These results suggest that a compromised cytoarchitecture and polarized trafficking of TGF-beta signaling molecules, ELF and Smad3 are involved in the pathogenesis of PBC as well as HCC.

Animals↗
PubMed2003

Disruption of transforming growth factor-beta signaling in ELF beta-spectrin-deficient mice.

Disruption of the adaptor protein ELF, a beta-spectrin, leads to disruption of transforming growth factor-beta (TGF-beta) signaling by Smad proteins in mice. Elf-/- mice exhibit a phenotype similar to smad2+/-/smad3+/- mutant mice of midgestational death due to gastrointestinal, liver, neural, and heart defects. We show that TGF-beta triggers phosphorylation and association of ELF with Smad3 and Smad4, followed by nuclear translocation. ELF deficiency results in mislocalization of Smad3 and Smad4 and loss of the TGF-beta-dependent transcriptional response, which could be rescued by overexpression of the COOH-terminal region of ELF. This study reveals an unexpected molecular link between a major dynamic scaffolding protein and a key signaling pathway.

Abnormalities, Multiple↗
PubMed1983

The spectrin membrane skeleton of normal and abnormal human erythrocytes: a review.

The erythrocyte membrane skeleton composed of spectrin, actin, and several other proteins is essential for the maintenance of the erythrocyte shape, reversible deformability, and membrane structural integrity in addition to controlling the lateral mobility of integral membrane proteins. In this review, we shall give an historical development of the current model of the erythrocyte membrane skeleton. We will then describe how the experimental technology developed to study the normal membrane skeleton has paved the way for the recent identification of alterations of skeletal protein interactions in hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis. We will conclude with a discussion of some of the more exciting and promising directions for future research that are currently being initiated in this vanguard field of cell biology.

Actins↗
PubMed1996

Cellular ATP depletion induces disruption of the spectrin cytoskeletal network.

Ischemia in vivo or ATP depletion in vitro result in disruption and cellular redistribution of the cortical F-actin cytoskeleton in epithelial cells. However, little is known regarding the effect of these two maneuvers on other components of the actin cytoskeleton. Because the spectrin (fodrin in epithelial cells)-based network links the actin cytoskeleton to the surface membrane, we have utilized a reversible model of ATP depletion in LLC-PK1 cells to study the effect of ATP depletion on fodrin and ankyrin. Under physiological conditions, both ankyrin and fodrin were largely Triton X-100 insoluble and colocalized immunofluorescently along the lateral membranes of LLC-PK1 cells. After ATP depletion, there was a rapid and duration-dependent increase in Triton X-100 solubility of both proteins. This was not true for villin and myosin 1, as Triton X-100 solubility was unaffected and reduced by ATP depletion, respectively. The increase in fodrin and ankyrin detergent solubility during ATP depletion was associated with cytosolic redistribution of the proteins, as determined using immunofluorescent techniques. Sucrose gradient fractionation and Western blot analysis of the Triton X-100-soluble fraction following ATP depletion revealed lack of association between fodrin and ankyrin. Furthermore, dual-label digital confocal immunofluorescent studies revealed lack of association of cytoplasmic ankyrin and fodrin following ATP depletion. Taken together, these data indicate that ATP depletion in LLC-PK1 cells leads to dissociation of both ankyrin and fodrin from the actin cytoskeleton. Furthermore, the two proteins dissociate from each other and redistribute throughout the cytoplasm.

Actins↗
PubMed1998

Expression of spectrin alphaI/50 hereditary elliptocytosis and its association with the alphaLELY allele.

Hereditary elliptocytosis (HE) is a group of hemolytic anemias characterized by the presence of elliptical erythrocytes. The underlying alterations lie in the proteins of the membrane skeleton. Defects of the alphaI domain of spectrin have been defined based on a decrease in the normal 80-kD alphaI domain and a concomitant increase in one or more lower molecular weight peptides. We have studied three Brazilian kindreds with black ancestry, who presented mild common spalphaI/50 HE. Our aim was to determine the molecular alteration responsible for the spalphaI/50 HE observed in these three kindreds and to evaluate the presence and influence of allele alphaLELY in the expression of this type of HE. In order to establish the molecular defect, exons 5, 6 and 11 were amplified and submitted to a nonradioactive single strand conformation polymorphism protocol. An identical band shift in exon 6 was observed in all 3 patients and their affected relatives. Direct sequencing of the amplification products of exon 6 showed the same molecular defect in all patients: a T-->C substitution, responsible for the L260P mutation. Allele alphaLELY, detected by PCR and restriction enzyme digestion, was present in the heterozygous form in the three propositi and was associated in trans with the elliptocytogenic mutation. Blood smears of the patients with HE and alphaLELY in trans showed pronounced elliptocytosis, poikilocytosis and a few small red cell fragments, whereas the blood smears of their relatives, who had HE without allele alphaLELY, showed mild common HE with a predominance of ovalocytes and the absence of poikilocytes. We conclude that allele alphaLELY does not lead to the worsening of clinical conditions when associated in trans with mild HE, but can be easily distinguished by a blood smear analysis. The predominance of the L260P mutation in the kindreds studied could be related to the colonization of Brazil during the slave trade by Africans from the Benin-Togo area, where this mutation is particularly common.

Adolescent↗
PubMed1987

Mapping of alpha-spectrin on distal mouse chromosome 1.

DNAs from different strains of inbred mice and feral Mus spretus were found to exhibit restriction fragment length polymorphisms (RFLP) when hybridized with a probe prepared from a c-DNA clone of the mouse alpha-spectrin (Spna-1) gene. Studies of five recombinant inbred strains and (C57BL/6 X M. spretus) F1 X C57BL/6 backcross mice demonstrated that these RFLPs were allelic and that Spna-1 is closely linked to Ly-9 and Ly-17 on the distal region of chromosome 1.

Alleles↗
PubMed1989

The B subunit of coagulation factor XIII is linked to renin and the Duffy blood group to alpha-spectrin on human chromosome 1.

Family linkage studies were used to detect two linkage relationships on human chromosome 1. The B subunit of coagulation factor XIII showed significant linkage to renin with a maximum lod score of 5.071 at a distance of 10 cM. Significant linkage was also shown between the Duffy blood group and alpha-spectrin with linkage results giving a combined lod score of 3.194 at 5 cM.

Blood Group Antigens↗
PubMed1986

Diminished extractable spectrin in the erythrocytes of a patient with 'sporadic' hereditary spherocytosis.

A 51-year-old white man of Irish extraction was found to have apparent 'sporadic' hereditary spherocytosis with a reticulocyte count of 6%. Twelve of his 13 siblings were examined and found to be haematologically normal. The patient's erythrocytes were found to have a diminished amount of spectrin as compared to his siblings and to unrelated controls. It is suggested that the proband may represent either a new mutant or possibly double heterozygosity for two inherited biochemical variants of the red cell membrane skeleton which individually give no haematological abnormalities.

Erythrocytes↗
PubMed1990

Immunohistochemical localization of nonerythroid spectrin (fodrin) in the sensory cells of the vestibular end organs of the rat and guinea pig.

Indirect immunofluorescence method was used to study presence and localization of nonerythroid spectrin (fodrin) in the vestibular sensory epithelia. Cryosections of the vestibular organs were treated by monoclonal antibody (mAb) reacting with mammalian fodrin. Strong mAb labelling was observed in the cuticular plate of the vestibular hair cells. The stereocilia were nonreactive and supporting cells showed only a weak reaction. Fodrin seems to have similar localization in the inner ear hair cells as actin (except stereocilia) and it appears to be the major component of the membrane skeleton in the inner ear hair cells. Fodrin-associated membrane skeleton may be involved in the hair cell function in several different ways.

Animals↗
PubMed2002

The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families.

Recent studies have characterised a family of giant cytoskeletal crosslinkers encoded by the short stop gene in Drosophila and the dystonin/BPAG1 and MACF1 genes in mammals. We refer to the products of these genes as spectraplakins to highlight the fact that they share features with both the spectrin and plakin superfamilies. These genes produce a variety of large proteins, up to almost 9000 residues long, which can potentially extend 0.4 micro m across a cell. Spectraplakins can interact with all three elements of the cytoskeleton: actin, microtubules and intermediate filaments. The analysis of mutant phenotypes in BPAG1 in mouse and short stop in Drosophila demonstrates that spectraplakins have diverse roles. These include linking the plasma membrane and the cytoskeleton, linking together different elements of the cytoskeleton and organising membrane domains.

Actins↗
PubMed2003

Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links.

The events responsible for repair of DNA interstrand cross-links in mammalian cells, the proteins involved and their interactions with each other are poorly understood. The present study demonstrates that the structural protein nonerythroid alpha spectrin (alphaSpIISigma*), present in normal human cell nuclei, plays an important role in repair of DNA interstrand cross-links. These results show that alphaSpIISigma* relocalizes to nuclear foci after damage of normal human cells with the DNA interstrand cross-linking agent 8-methoxypsoralen plus ultraviolet A (UVA) light and that FANCA and the known DNA repair protein XPF localize to the same nuclear foci. That alphaSpIISigma* is essential for this re-localization is demonstrated by the finding that in cells from patients with Fanconi anemia complementation group A (FA-A), which have decreased ability to repair DNA interstrand cross-links and decreased levels of alphaSpIISigma*, there is a significant reduction in formation of damage-induced XPF as well as alphaSpIISigma* nuclear foci, even though levels of XPF are normal in these cells. In corrected FA-A cells, in which levels of alphaSpIISigma* are restored to normal, numbers of damage-induced nuclear foci are also returned to normal. Co-immunoprecipitation studies show that alphaSpIISigma*, FANCA and XPF co-immunoprecipitate with each other from normal human nuclear proteins. These results demonstrate that alphaSpIISigma*, FANCA and XPF interact with each other in the nucleus and indicate that there is a close functional relationship between these proteins. These studies suggest that an important role for alphaSpIISigma* in the nucleus is to act as a scaffold, aiding in recruitment and alignment of repair proteins at sites of damage.

Blotting, Western↗
PubMed2002

Myne-1, a spectrin repeat transmembrane protein of the myocyte inner nuclear membrane, interacts with lamin A/C.

Mutations in the genes encoding the inner nuclear membrane proteins lamin A/C and emerin produce cardiomyopathy and muscular dystrophy in humans and mice. The mechanism by which these broadly expressed gene products result in tissue-specific dysfunction is not known. We have identified a protein of the inner nuclear membrane that is highly expressed in striated and smooth muscle. This protein, myne-1 (myocyte nuclear envelope), is predicted to have seven spectrin repeats, an interrupted LEM domain and a single transmembrane domain at its C-terminus. We found that myne-1 is expressed upon early muscle differentiation in multiple intranuclear foci concomitant with lamin A/C expression. In mature muscle, myne-1 and lamin A/C are perfectly colocalized, although colocalization with emerin is only partial. Moreover, we show that myne-1 and lamin A/C coimmunoprecipitate from differentiated muscle in vitro. The muscle-specific inner nuclear envelope expression of myne-1, along with its interaction with lamin A/C, indicates that this gene is a potential mediator of cardiomyopathy and muscular dystrophy.

Amino Acid Sequence↗
PubMed1994

Plasmodium falciparum proteinases: cloning of the putative gene coding for the merozoite proteinase for erythrocyte invasion (MPEI) and determination of hydrolysis sites of spectrin by Pf37 proteinase.

Numerous proteinase activities have been shown to be essential for the survival of Plasmodium falciparum. One approach to antimalarial chemotherapy, would be to block specifically one or several of these activities, by using compounds structurally analogous to the substrates of these proteinases. Such a strategy requires a detailed knowledge of the active site of the proteinase, in order to identify the best substrate for the proteinase. Aiming at developing such a strategy, two proteinases previously identified in our laboratory, were chosen for further characterization of their molecular structure and properties: the merozoite proteinase for erythrocytic invasion (MPEI), involved in the erythrocyte invasion by the merozoites, and the Pf37 proteinase, which hydrolyses human spectrin in vitro.

Animals↗
PubMed1996

VH and VL gene complexes encoding an anti-spectrin antibody are defined by nucleotide sequencing of cDNA from a hybridoma generated from Hu-PBL-SCID mouse.

Previously we reported that human imunocompetent cells engrafted into scid mice mount a sustained and vigorous humoral immune response to murine erythrocytes. One of the dominant and consistently observed reactivity pattern of these antibodies in immunoblot analysis is with the alpha and beta isoforms of spectrin. In order to define the human xenoreactive response more completely, a hybridoma was generated (from a hu-PBL-scid mouse) whose antibody reacted with two high molecular weight species 225 to 250 kDa. We report here that this conserved antibody species reacts with both the murine and human erythrocyte proteins and cDNA nucleotide sequence analysis of the light and heavy chain genes encoding this antibody reveals that the light chain variable region gene has been previously observed in association with an autoreactive antibody. In addition to characterizing a conserved human B cell clonotype this is the first report of a human monoclonal antibody being generated from the hu-PBL-scid model using the standard hybridoma technology.

Amino Acid Sequence↗
PubMed1980

Does the conformation of Mg-ATPase (spectrin-dependent ATPase) influence the passive permeability to K+?

The processing of human erythrocytes disclosed changes in Mg-ATPase activity following action of Pb2+ and Nile blue, and changes of permeability of K+ after treatment with Nile blue. The obtained results and those from previous papers can be summarized as follows : Substances decreasing the activity of stimulated membrane Mg-ATPase (spectrin-dependent ATPase) in red blood cells increase the passive permeability to K+, and substances increasing the stimulated Mg-ATPase activity decrease the passive permeability to K+. A hypothesis is proposed that the conformation of Mg-ATPase is secondarily reflected in the state of the proper path for K+ transport through the membrane; thus the rate of passive permeability to K+ is influenced.

Adenosine Triphosphatases↗
PubMed2004

Band 3 is a target protein of spectrin's E2/E3 activity: implication for sickle cell disease and normal red blood cell aging.

We have demonstrated that a 125 kDa red blood cell (RBC) membrane protein, being a target of spectrin's E2/E3 activity, is ubiquitinated band 3. This demonstration was based on copurification of this biotinylated-ubiquitinated protein with band 3, immunoprecipitation with band 3 antibody and analysis of proteins associated with strepavidin sepharose by micro liquid chromatography coupled to tandem mass spectrometry (microLC/MS/MS). Further, we demonstrated the presence of ubiquitinated band 3 in vivo by Western blotting of purified band 3 with a monoclonal antibody (FK2) against ubiquitin. The implications of these results for sickle cell disease and RBC aging are discussed.

Anemia, Sickle Cell↗
PubMed2004

Pseudohypoaldosteronism type 1 and the genes encoding prostasin, alpha-spectrin, and Nedd4.

Pseudohypoaldosteronism type 1 (PHA1), a rare disorder of infancy, presents with potential life-threatening salt wasting and failure to thrive. Thus far, PHA1 has been attributed to mutations affecting the mineralocorticoid receptor or any of the three subunits assembling the amiloride-sensitive epithelial sodium channel (ENaC). However, a lot of patients with a phenotype resembling PHA1, show no defects in these proteins, making it likely that further genes are involved in the aetiology of this disease. Recent studies have elucidated additional participants (alpha-spectrin and members of the families of transmembrane serine proteases, ubiquitin-protein ligases, and serum- and glucocorticoid-regulated kinases, respectively) regulating and/or interacting in the complex pathway of sodium retention in the amiloride-sensitive distal nephron. This led us to investigate whether PHA1 can also be associated with mutations in some of these genes. Our data suggest that at least the prostasin gene might be excluded as a causative locus.

Endosomal Sorting Complexes Required for Transport↗