SEARCH · Search PubMed

Results for “Filamins”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources

PubMed2026

A novel FLNA p.Pro2469Ser variant is associated with impaired T and NK cell function and immune dysregulation.

FLNA encodes filamin A, a ubiquitously expressed actin-binding cytoskeletal protein that cross-links actin filaments and links them to membrane-associated signaling complexes. Although FLNA has been implicated in T-cell signaling and regulatory T-cell development in murine models, its role in human immune-cell function remains incompletely understood. Here, we investigated the immunological phenotype associated with a novel hemizygous FLNA variant identified in a pediatric patient presenting with recurrent infections and inflammatory manifestations. Whole-exome sequencing revealed a hemizygous c.7405C>T (p.Pro2469Ser) variant in FLNA, which was confirmed by Sanger sequencing. Its potential impact on immune-cell function and cytoskeletal organization was evaluated using confocal microscopy, flow cytometry, and molecular assays. Patient-derived T cells showed impaired activation and proliferation following CD3/CD28 and IL-2 stimulation, accompanied by reduced CD25 and CD69 upregulation. CD4+ T cells also exhibited reduced IFN-γ, TNF-α, and IL-2 production after stimulation. Despite elevated basal phospho-STAT5 levels, IL-2-induced STAT5 phosphorylation and TCR-associated signaling responses, including pZAP70, pLCK, and p38 MAPK activation, were attenuated. Confocal imaging together with image-based quantification demonstrated altered cortical cytoskeletal organization in patient T cells despite preserved FLNA expression. In parallel, NK cells showed impaired activation responses and reduced cytotoxic activity under the assay conditions used. Increased apoptosis was observed in CD4⁺, CD8⁺, and NK-cell populations. Inflammatory cytokines were elevated in plasma and colonic tissue, whereas colonic ZO-1 and FLNA expression were reduced. Collectively, these findings indicate that the FLNA p.Pro2469Ser variant is associated with altered immune-cell signaling, disturbed cortical cytoskeletal organization, and immune dysregulation. This study expands the phenotypic spectrum linked to FLNA variants and supports a role for filamin A in human immune-cell regulation.

Humans↗

PubMed2003

Up-regulation of the D1 dopamine receptor-interacting protein, calcyon, in patients with schizophrenia.

BACKGROUND: The dopamine hypothesis remains a prominent influence on research into the pathogenesis of schizophrenia, yet the presence of consistent schizophrenia-linked abnormalities in the presynaptic components of the dopamine system or in dopamine receptors still remains a matter of debate. The present study focuses on a recently recognized group of dopamine receptor-interacting proteins as possible novel sites of dysfunction in schizophrenia. Specifically, we examined whether the D1 dopamine receptor-interacting protein calcyon and the D2 dopamine receptor-interacting proteins filamin-A and spinophilin are affected in the dorsolateral prefrontal cortex of patients with schizophrenia. METHODS: Slot blots of dorsolateral prefrontal cortical tissue were used to compare the levels of the 3 proteins of interest in control, schizophrenic, bipolar, and major depression groups (n = 15 per group). The nonschizophrenic psychiatric groups were included to determine the specificity of the detected abnormalities. RESULTS: The dorsolateral prefrontal cortex in schizophrenic patients displayed nearly twice the normal levels of calcyon, whereas filamin-A and spinophilin levels were unaltered. Patients with bipolar disorder or major depression showed no changes in all 3 proteins examined. CONCLUSION: Our findings provide the first evidence that abnormalities in the dopamine system of patients with schizophrenia may lie in altered levels of dopamine receptor-interacting proteins.

Animals↗

PubMed2006

Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia.

Frontometaphyseal dysplasia (FMD) belongs to a group of overlapping skeletal dysplasias, the common molecular basis of which are mutations of FLNA, the gene encoding filamin A. The nature of the mutation has been considered the major determinant of the phenotype within this group that comprises the otopalatodigital syndromes (OPD1, OPD2) and Melnick-Needles syndrome besides FMD. However, to date the molecular pathomechanisms are not well understood. In FMD only few FLNA mutations have been reported which do not cluster in a specific region of the protein. We report on a novel de novo mutation 5182G --> T in exon 31 of the FLNA gene in a girl with manifestations of FMD and OPD1. This mutation is predicted to lead to the exchange of a highly conserved glycine residue at position 1,728 by cysteine (G1728C) in repeat 15 of the filamin A rod domain. In a second family with FMD, we identified a known mutation (S1186L) in a mother and her son. In contrast to most previous reports on manifesting females or carriers of the FLNA-related skeletal dysplasias, the affected females presented here showed only mild to moderate skewing of X-inactivation against the mutant allele. Our data may indicate that in females, genotype-phenotype correlation between certain FLNA mutations and OPD1 and FMD, respectively, is less strict than previously assumed. We propose that X-inactivation is an important epigenetic modifier of the phenotype in females with the FLNA-related skeletal dysplasias.

Abnormalities, Multiple↗

PubMed2006

Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity.

Frontometaphyseal dysplasia is an X-linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X-linked gene, FLNA. We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin-binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X-inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder.

Adult↗

PubMed1990

Redistribution of membranes and cytoskeletal proteins in chicken oxyntic cells during the HCl secretory cycle: ultrastructural and immunofluorescence study.

Changes in ultrastructure and cytoskeletal organization by avian oxyntic cells, at the onset of HCl secretion, were analysed. Cells in resting state, induced by fasting and cimetidine, were compared with histamine stimulated secreting cells. Ultrastructural studies were done by transmission electron microscopy; the distribution of prekeratin, myosin, and filamin-like protein, by immunofluorescence; and that of F-actin using FITC-phalloidin. Resting cells show short pericellular clefts. These are increasingly deepened in secreting cells by a reorganization of the lateral cell borders involving displacement of the junctional complexes toward the cell base and incorporation of the tubular system to the luminal plasma membrane. In secreting cells, the processes of the secretory surface are concentrated in a pericellular groove. Histamine stimulation induces a drastic redistribution of cytoskeletal proteins. In chicken oxyntic cells, in addition to the F-actin cytoskeleton associated with the membranes of the secretory surface, there is a cytoskeletal ring containing F-actin, myosin, and a filamin-like protein, located at the level of the junctional complexes. In resting cells, filaments and masses of cytoskeletal matrix are associated with the zonula adherens. In secreting cells, the junctional complexes maintain their association with the filamentous ring, while the amorphous matrix is replaced by microfilaments that support the processes of the luminal surface. Intermediate filaments form a peripheral ring probably associated with the zonula adherens, and project from the ring toward the cell cytoplasm. Thus, with the onset of HCl secretion, the apical cytoskeletal ring of resting cells displaces toward the cell base. A role for this cytoskeletal ring in the changes in shape parallel to HCl secretion is discussed.

Actins↗

PubMed1994

Occurrence of fibers and their association with talin in the cleavage furrows of PtK2 cells.

PtK2 cells of exceptionally large size were microinjected with fluorescently labeled probes for actin, myosin, filamin, and talin in order to follow the assembly of the contractile proteins into the cleavage furrows. Whereas in cells of normal size, there is usually a diffuse pattern of localization of proteins in the cleavage furrow, in these large, flat cells the labeled proteins localized in fibers in the cleavage furrow. Often, the fibers were striated in a pattern comparable to that measured in the stress fibers of the same cell type. The presence of talin in discrete plaques along fibers in the cleavage furrows of the large cells suggests a further similarity between cleavage furrow and stress fiber structure. The presence of filamin in the cleavage furrows also suggests the possibility of an overlapping mechanism in addition to that of a talin mediated mechanism for the attachment of actin filaments to the cell surfaces in the cleavage furrow. A model is presented that emphasizes the interrelationships between stress fibers, myofibrils, and cleavage furrows.

Actin Cytoskeleton↗

PubMed2004

Global gene expression analysis comparing bovine blastocysts flushed on day 7 or produced in vitro.

In vitro produced (IVP) bovine embryos have darker cytoplasm, reduced buoyant density, fragile zonae pellucidae, chromosomal abnormalities, higher pregnancy failure rates, and altered gene expression compared to embryos produced in vivo. Characterization of early deviations in gene expression would enable us to better understand the biology of early embryo development and improve in vitro culture systems. Here we compared gene expression between Day 7 blastocysts generated in TCM199 with 5% FBS and Day 7 in vivo derived blastocysts and using suppression-subtractive hybridization (SSH). Pools of 25 embryos for both driver and tester were used in the RNA extraction process. The subtracted products were cloned and subjected to differential hybridization screening analysis. cDNAs were isolated, single-pass sequenced, and subjected to BLAST search. Of 32 in vivo ESTs (expressed sequence tags) that provided sequence information, 30 matched homologous sequences in GenBank. Of 32 in vitro ESTs, 22 provided specific matches while the remaining ten represented novel transcripts. Two in vivo ESTs, galectin-1 and fibronectin, and one in vitro EST, filamin A, were further characterized using real-time quantitative PCR. To further examine the reproducibility of the SSH data, three different pools of embryos with each pool containing ten embryos produced from each of the following production systems, namely, in vivo, IVP in TCM199 with 5% FBS and CR1aa with 5% FBS were used for real-time reverse transcription-polymerase chain reaction (RT-PCR) confirmation studies. Significant increases in the expression level of galectin-1 and fibronectin were observed in the in vivo derived blastocysts compared to blastocysts produced in TCM199 with 5% FBS and CR1aa cultures. No significant difference in filamin A expression was found between blastocysts produced in vivo and those derived from either of the in vitro production systems. We conclude that these techniques are useful to characterize the transcriptome of the early preattachment embryo and observed deviations in mRNA expression may partially explain the differences in quality between in vivo and IVP embryos.

Animals↗

PubMed2000

Aluminum modifies the viscosity of filamentous actin solutions as measured by optical displacement microviscometry.

A microtechnique has been developed that is capable of measuring the viscosity of filamentous actin (F-actin) solutions. This method, called optical displacement microviscometry (ODM), was utilized to determine the changes in viscosity of solutions of rabbit muscle, human platelet, and maize pollen actin when measured in the absence and presence of aluminum. Measurements demonstrated that the viscosity of the different actin solutions decreased with aluminum concentration. In contrast, increases in viscosity were observed when aluminum was added to F-actin solutions containing filamin (chicken gizzard), a protein that bundles actin filaments. Confocal fluorescence imaging of pure actin solutions in the presence of aluminum showed a disrupted actin network composed of fragmented actin filaments in the form of small aggregates. In contrast, in the presence of filamin, aluminum promoted the formation of thicker actin filaments. These measurements demonstrate that aluminum can affect actin filaments differentially depending on the presence of an actin-binding protein. In addition, a strong correlation is observed between the changes in viscosity as measured by ODM and the thickness and assembled state of bundles of actin filaments.

Actins↗

PubMed2000

Kinetic determination of focal adhesion protein formation.

I examined the binding kinetics between integrin (alpha(IIb)beta(3)) and purified focal adhesion proteins, including alpha-actinin, filamin, vinculin, talin, and F-actin. Using static light-scatter technique, I observed affinities of the order talin > filamin > F-actin > alpha-actinin > (talin when bound to vinculin) which were lower when integrin was complexed with fibronectin. No binding between integrin and vinculin was detected. The calculated dissociation constants (K(d)) ranged between 0.4 microM and 5 microM. These results in part confirm previously published data using different methods. The modest affinity with which the focal adhesion proteins interact in vitro might be indicative of how cells, e.g., thrombocytes, gain a high degree of versatility and velocity.

Actinin↗

PubMed1999

Identification and immunolocalization of actin cytoskeletal components in light- and dark-adapted octopus retinas.

Photoreceptors in the octopus retina are of the rhabdomeric type, with rhabdomeres arising from the plasma membrane on opposite sides of the cylindrical outer segment. Each rhabdomere microvillus has an actin filament core, but other actin-binding proteins have not been identified. We used immunoblotting techniques to identify actin-binding proteins in octopus retinal extracts and immunofluorescence microscopy to localize the same proteins in fixed tissue. Antibodies directed against alpha-actinin and vinculin recognized single protein bands on immunoblots of octopus retinal extract with molecular weights comparable to the same proteins in other tissues. Anti-filamin identified two closely spaced bands similar in molecular weight to filamin in other species. Antibodies to the larger of the Drosophila ninaC gene products, p174, identified two bands lower in molecular weight than p174. Anti-villin localized a band that was significantly less in molecular weight than villin found in other cells. Epifluorescence and confocal microscopy were used to map the location of the same actin-binding proteins in dark- and light-adapted octopus photoreceptors and other retinal cells. Antibodies to most of the actin-binding proteins showed heavy staining of the photoreceptor proximal/supportive cell region accompanied by rhabdom membrane and rhabdom tip staining, although subtle differences were detected with individual antibodies. In dark-adapted retinas anti-alpha-actinin stained the photoreceptor proximal/supportive cell region where an extensive junctional complex joins these two cell types, but in the light, immunoreactivity extended above the junctional complex into the rhabdom bases. Most antibodies densely stained the rhabdom tips but anti-villin exhibited a striated pattern of localization at the tips. We believe that the actin-binding proteins identified in the octopus retina may play a significant role in the formation of new rhabdomere microvilli in the dark. We speculate that these proteins and actin remain associated with an avillar membrane that connects opposing sets of rhabdomeres in light-adapted retinas. Association of these cytoskeletal proteins with the avillar membrane would constitute a pool of proteins that could be recruited for rapid microvillus formation from the previously avillar region.

Actinin↗

PubMed1985

Immunohistochemical evaluation of factor VIII related antigen, filament proteins and lectin binding in haemangiomas.

Immunohistochemical identification of factor VIII related antigen (F VIII RAG) filament proteins (actin, myosin, filamin, vimentin and desmin) and lectin binding patterns of Con A, PNA, SBA, WGA, RCA-1, UEA-1 and DBA in the endothelial cells and the muscular layers of haemangiomas and normal blood vessels are reported, using paraffin sections with the HRP method. The endothelial cells of haemangiomas were usually strongly positive to F VIII RAG as were those from capillary vessels and other small vessels. Some of the endothelium from haemangiomas and angiokeratomas was negative for factor VIII. The vessel walls of hemangiomas showed staining slightly positive for microfilaments (actin, myosin, filamin). The smooth muscle layer in small vessels showed a more marked staining with actin. Vimentin and desmin reactions in the vessel walls of haemangioma and in normal vessels were slight or moderate. UEA-1 lectin binding was constantly positive in endothelial cells from hemangiomas and in blood vessels. SBA and WGA binding appeared in the border layer of endothelium in haemangiomas and normal vessels.

Actins↗

PubMed1985

The thin filaments of smooth muscles.

Contraction in vertebrate smooth and striated muscles results from the interaction of the actin filaments with crossbridges arising from the myosin filaments. The functions of the actin based thin filaments are (1) interaction with myosin to produce force; (2) regulation of force generation in response to Ca2+ concentration; and (3) transmission of the force to the ends of the cell. The major protein components of smooth muscle thin filaments are actin, tropomyosin and caldesmon, present in molar ratios of 28:4:1 respectively. Other smooth muscle proteins which may be associated with the thin filaments in the cell are filamin, vinculin, alpha-actinin, myosin light chain kinase and calmodulin. We have reviewed the structural and functional properties of these proteins and where possible we have suggested what their function and mechanism of action may be. We propose that actin and tropomyosin are involved in the force producing interaction with myosin, and that this interaction is controlled by a Ca2+-dependent mechanism involving caldesmon, tropomyosin and calmodulin. Vinculin, alpha-actinin and filamin appear to be involved in the attachment of the thin filaments to the cell membrane and their spatial organization within the cell. We conclude that the filaments of smooth muscles share many common properties with those from skeletal muscle, but that they are also quite distinct in terms of both their caldesmon based regulatory mechanism and their mode of organization into a contractile apparatus.

Actinin↗

PubMed1987

Diversity in smooth muscle thin filament composition.

Two classes of smooth muscle thin filament can be identified and separated based on their interaction with antibodies specific either to filamin or to caldesmon. One type is composed of actin, tropomyosin and filamin and the other of actin, tropomyosin and caldesmon.

Actins↗

PubMed2005

Periventricular heterotopia.

Periventricular heterotopia (PH) is clinically diagnosed on the basis of the radiographic characteristics of heterotopic nodules composed of disorganized neurons along the lateral ventricles of the brain. Epilepsy is the main presenting symptom of patients with PH. Behaviorally, patients generally are of normal intelligence, although there have been associated findings of learning disabilities, namely, dyslexia. Two genes responsible for PH have been identified: FilaminA, which encodes for the protein filamin A, and ARFGEF2, which encodes for the vesical transport-regulating protein ARFGEF2. The much more common X-linked dominant form of this disorder is due to filamin A, affects females, and is typically lethal in males. A much rarer autosomal recessive form due to ARFGEF2 mutations leads to microcephaly and developmental delay in addition to PH. Cell motility, adhesion defects, and weakening along the neuroepithelial lining may result from defects in these genes during cortical development and contribute to PH, but the mechanisms are not clear yet. Treatment of PH is largely symptomatic, following basic principles for epilepsy management and genetic counseling.

Animals↗

PubMed1999

Calponin interaction with alpha-actinin-actin: evidence for a structural role for calponin.

The purpose of this study was to address the paradox of calponin localization with alpha-actinin and filamin, two proteins with tandem calponin homology (CH) domains, by determining the effect of these proteins on the binding of calponin to actin. The results show that actin can accommodate near-saturating concentrations of either calponin and alpha-actinin or calponin and filamin with little change or no change in ligand affinity. Little direct interaction occurred between alpha-actinin and calponin in the absence of actin, so this effect is not likely to explain the co-distribution of these proteins. Calponin, like alpha-actinin, induced elastic gel formation when added to actin. When alpha-actinin was added to newly formed calponin/actin gels, no change was seen in the mechanical properties of the gel compared to calponin and actin alone. However, when calponin was added to newly formed alpha-actinin/actin gels, the resulting gel was much stronger than the gels formed by either ligand alone. Furthermore, gels formed by the addition of calponin to alpha-actinin/actin exhibited a phenomenon known as strain hardening, a characteristic of mechanically resilient gels. These results add weight to the concept that one of the functions of calponin is to stabilize the actin cytoskeleton.

Actinin↗

PubMed2003

Salmonella effectors translocated across the vacuolar membrane interact with the actin cytoskeleton.

A family of nine Salmonella typhimurium type III secretion effectors with a conserved amino-terminus have been defined. Three family members (SifA, SifB and SseJ) have previously been demonstrated to localize to the Salmonella-containing vacuole and to Salmonella-induced filaments. In contrast, we demonstrate that two other family members, SspH2 and SseI, co-localized with the polymerizing actin cytoskeleton. These proteins also interacted with the mammalian actin cross-linking protein filamin in the yeast two-hybrid assay through their highly conserved amino-terminal domains. This amino-terminus was sufficient to direct localization to the polymerizing actin cytoskeleton, suggesting that the interaction with filamin is important for this subcellular localization. In addition, SspH2 co-localized with vacuole-associated actin polymerizations (VAP) induced by intracellular bacteria through the Salmonella pathogenicity island (SPI)-2 type III secretion system (TTSS). SspH2 interacted with the actin-binding protein profilin in the yeast two-hybrid assay and by affinity chromatography. This interaction was highly specific to SspH2 and was mediated by its carboxy-terminus. Furthermore, SspH2 inhibited the rate of actin polymerization in vitro, suggesting that it functions to reduce or remodel VAP. Strains with mutations in sspH2 and sseI retained the ability to form VAP. However, a third intracellular virulence factor, spvB, which ADP-ribosylates actin, strongly inhibited VAP formation in HeLa cells, suggesting a more subtle effect for SspH2 and SseI on the actin cytoskeleton.

Actins↗

PubMed1989

Actin polymerization induces a shape change in actin-containing vesicles.

We have encapsulated actin filaments in the presence and absence of various actin-binding proteins into lipid vesicles. These vesicles are approximately the same size as animal cells and can be characterized by the same optical microscopic and mechanical techniques used to study cells. We demonstrate that the initially spherical vesicles can be forced into asymmetric, irregular shapes by polymerization of the actin that they contain. Deformation of the vesicles requires that the actin filaments be on average at least approximately 0.5 micron long as shown by the effects of gelsolin, an actin filament-nucleating protein. Filamin, a filament-crosslinking protein, caused the surfaces of the vesicles to have a smoother appearance. Heterogeneous distribution of actin filaments within the vesicles is caused by interfilament interactions and modulated by gelsolin and filamin. The vesicles provide a model system to study control of cell shape and cytoskeletal organization, membrane-cytoskeleton interactions, and cytomechanics.

Actins↗

PubMed2006

Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration.

The receptor tyrosine kinase Ror2 plays important roles in developmental morphogenesis. It has recently been shown that Ror2 mediates Wnt5a-induced noncanonical Wnt signaling by activating the Wnt-JNK pathway and inhibiting the beta-catenin-TCF pathway. However, the function of Ror2 in noncanonical Wnt signaling leading to cell migration is largely unknown. We show, using genetically different or manipulated cultured cells, that Ror2 is critical for Wnt5a-induced, but not Wnt3a-induced, cell migration. Ror2-mediated cell migration requires the extracellular cysteine-rich domain (CRD), which is the binding site for Wnt5a, and the cytoplasmic proline-rich domain (PRD) of Ror2. Furthermore, Ror2 can mediate filopodia formation via actin reorganization, irrespective of Wnt5a, and this Ror2-mediated filopodia formation requires the actin-binding protein filamin A, which associates with the PRD of Ror2. Intriguingly, disruption of filopodia formation by suppressing the expression of either Ror2 or filamin A inhibits Wnt5a-induced cell migration, indicating that Ror2-mediated filopodia formation is essential for Wnt5a-induced cell migration.

Adaptor Proteins, Signal Transducing↗