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PubMed2001

Interaction between platelet glycoprotein Ibalpha and filamin-1 is essential for glycoprotein Ib/IX receptor anchorage at high shear.

The interaction of the glycoprotein (GP) Ib-V-IX receptor complex with the membrane skeleton of platelets is dependent on a specific interaction between the cytoplasmic tail of GPIbalpha and filamin-1. This interaction has been proposed to regulate key aspects of platelet function, including the ligand binding of GPIb-V-IX and the ability of the cells to sustain adhesion to von Willebrand factor (vWf) under high shear. In this study we have examined sequences in the GPIbalpha intracellular domain necessary for interaction of the receptor with filamin-1. We have identified two adjacent sequences involving amino acids 557-568 and 569-579 of the GPIbalpha cytoplasmic domain that are critical for normal association between the receptor complex and filamin-1. Under flow conditions, Chinese hamster ovary (CHO) cells expressing these two mutant receptors exhibited an increase in translocation velocity that was associated with increased cell detachment from the vWf matrix at high shear. The shear-dependent acceleration in velocity of mutant Delta557-568 and Delta569-579 CHO cells was associated with a critical defect in receptor anchorage, evident from significant extraction of GPIb-IX from the CHO cell membrane at high shear. These studies define a critical role for amino acids within the 557-579 sequence of GPIbalpha for interaction with filamin-1.

Amino Acid Sequence↗
PubMed1986

Localization of filamin in smooth muscle.

The distribution of contractile and cytoskeletal proteins in smooth muscle has been mapped by immunocytochemical methods, with special reference to the localization of the actin-binding protein, filamin. Immunolabeling of ultrathin sections of polyvinylalcohol-embedded smooth muscle distinguished two domains in the smooth muscle cell: (a) actomyosin domains, made up of continuous longitudinal arrays of actin and myosin filaments, and (b) longitudinal, fibrillar, intermediate filament domains, free of myosin but containing actin and alpha-actinin-rich dense bodies. Filamin was found to be localized specifically in the latter intermediate filament-actin domains, but was excluded from the core of the dense bodies. Filamin was also localized close to the cell border at the inner surface of the plasmalemma-associated plaques. In isolated cells the surface filamin label showed a rib-like distribution similar to that displayed by vinculin. It is speculated that the two domains distinguished in these studies may reflect the existence of two functionally distinct systems: an actomyosin system required for contraction and an intermediate filament-actin system, with associated gelation proteins, that is responsible, at least in part, for the slow relaxation and tone peculiar to smooth muscle.

Animals↗
PubMed1990

Brownian motion of inert tracer macromolecules in polymerized and spontaneously bundled mixtures of actin and filamin.

By use of light microscopy and fluorescence photobleaching recovery, we have studied (a) structures that form in a system composed of copolymerized rabbit muscle actin and chicken gizzard filamin and (b) the Brownian motion of inert tracer macromolecules in this matrix. We have used as tracers size-fractionated fluorescein-labeled ficoll and submicron polystyrene latex particles. In F-actin solutions, the relative diffusion coefficient of the tracer was a decreasing function of both tracer size and actin concentration. Also, a percolation transition for latex particle mobility was found to follow a form suggested by Ogston (Ogston, A. G. 1958. Trans. Faraday Soc. 54:1754-1757) for random filament matrices. The inclusion of filamin before polymerization resulted in increased tracer mobility. Below a filamin dimer-to-actin monomer ratio of 1:140, no structural features were observed in the light microscope. At or above this ratio for all actin concentrations tested, a three-dimensional network of filament bundles was clearly discriminated. Latex particles were always excluded from the bundles. By use of a dialysis optical cell in which polymerization could be initiated with very little hydrodynamic stress, we found that filamin can spontaneously bundle F-actin. A simple physical picture explains how dynamics can affect the structural result of coassembly and provides a further hypothesis on the balance between random filament cross-linking and large-scale bundling. Control of this balance may be important in cytoplasmic motile events.

Actins↗
PubMed2000

Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein.

Mutations in genes encoding for the sarcoglycans, a subset of proteins within the dystrophin-glycoprotein complex, produce a limb-girdle muscular dystrophy phenotype; however, the precise role of this group of proteins in the skeletal muscle is not known. To understand the role of the sarcoglycan complex, we looked for sarcoglycan interacting proteins with the hope of finding novel members of the dystrophin-glycoprotein complex. Using the yeast two-hybrid method, we have identified a skeletal muscle-specific form of filamin, which we term filamin 2 (FLN2), as a gamma- and delta-sarcoglycan interacting protein. In addition, we demonstrate that FLN2 protein localization in limb-girdle muscular dystrophy and Duchenne muscular dystrophy patients and mice is altered when compared with unaffected individuals. Previous studies of filamin family members have determined that these proteins are involved in actin reorganization and signal transduction cascades associated with cell migration, adhesion, differentiation, force transduction, and survival. Specifically, filamin proteins have been found essential in maintaining membrane integrity during force application. The finding that FLN2 interacts with the sarcoglycans introduces new implications for the pathogenesis of muscular dystrophy.

Amino Acid Sequence↗
PubMed2004

Cloning, expression, purification, crystallization and preliminary crystallographic analysis of gamma-filamin repeat 23.

Human gamma-filamin is a protein of 2705 amino-acid residues that localizes mainly in the myofibrillar Z-disc and to smaller extent in the subsarcolemmal region of striated muscle cells. gamma-Filamin consists of an N-terminal actin-binding domain followed by a long rod-shaped region. The rod-shaped region consists of 24 immunoglobulin-like domains that form a platform for interaction with different transmembrane, cell-signalling and cytoskeletal proteins. gamma-Filamin repeat 23 was indicated as being necessary for binding to the muscle-specific subsarcolemmal proteins gamma- and delta-sarcoglycan and the myofibrillar protein FATZ1. The recombinant gamma-filamin repeat 23 was crystallized using the hanging-drop vapour-diffusion method, which yielded needle-shaped diffraction-quality crystals. Diffraction data were collected to 2.05 angstroms resolution using 1.2 angstroms wavelength synchrotron radiation. Preliminary structural analysis shows one molecule, with predominantly beta secondary-structure elements, per asymmetric unit.

Actins↗
PubMed2006

Actin-binding protein filamin A is displayed on the surface of human neuroblastoma cells.

We previously reported the identification of natural human IgM antibodies, which recognize a M(r) 260 000 surface protein (NB-p260) and induce both complement-mediated cytotoxicity and apoptosis of human neuroblastoma cells. NB-p260 was shown to belong to the family of filamin proteins. Filamin A is a high molecular weight actin-binding protein, previously thought to be only located intracellularly. Here we show that NB cells as well as three NB-unrelated human cell lines express filamin A also on the cell surface. Our findings suggest new biological functions for filamins, including a role as mediators in anti-NB IgM-induced apoptosis, and they add to the growing body of evidence of the interaction of cytoskeletal proteins with the extracellular matrix.

Actins↗
PubMed1992

Localization and identification of actin structures involved in the filamin-actin interaction.

The interface between gizzard filamin and skeletal muscle actin was located on the actin monomer. Conserved sequences 105-120 and 360-372, in the actin subdomain 1 near the myosin binding sites, were involved in this interaction. The corresponding peptides for these sequences were each found to bind filamin and compete in the actin-filamin interaction. When these two peptides were used together in the presence of filamin and filamentous actin, they dissociated sedimentable complexes formed by these two proteins.

Actins↗
PubMed2007

Filamin links cell shape and cytoskeletal structure to Rho regulation by controlling accumulation of p190RhoGAP in lipid rafts.

Cytoskeleton-dependent changes in the activity of the small GTPase Rho mediate the effects of cell shape on cell function; however, little is known about how cell spreading and related distortion of the cytoskeleton regulate Rho activity. Here we show that rearrangements of the actin cytoskeleton associated with early phases of cell spreading in human microvascular endothelial (HMVE) cells suppress Rho activity by promoting accumulation of p190RhoGAP in lipid rafts where it exerts its Rho inhibitory activity. p190RhoGAP is excluded from lipid rafts and Rho activity increases when cell rounding is induced or the actin cytoskeleton is disrupted, and p190RhoGAP knockdown using siRNA prevents Rho inactivation by cell spreading. Importantly, cell rounding fails to prevent accumulation of p190RhoGAP in lipid rafts and to increase Rho activity in cells that lack the cytoskeletal protein filamin. Moreover, filamin is degraded in spread cells and cells that express a calpain-resistant form of filamin exhibit high Rho activity even when spread. Filamin may therefore represent the missing link that connects cytoskeleton-dependent changes of cell shape to Rho inactivation during the earliest phases of cell spreading by virtue of its ability to promote accumulation of p190RhoGAP in lipid rafts.

Cell Line↗
PubMed2005

Dynamic interactions of Fc gamma receptor IIB with filamin-bound SHIP1 amplify filamentous actin-dependent negative regulation of Fc epsilon receptor I signaling.

The engagement of high affinity receptors for IgE (FcepsilonRI) generates both positive and negative signals whose integration determines the intensity of mast cell responses. FcepsilonRI-positive signals are also negatively regulated by low affinity receptors for IgG (FcgammaRIIB). Although the constitutive negative regulation of FcepsilonRI signaling was shown to depend on the submembranous F-actin skeleton, the role of this compartment in FcgammaRIIB-dependent inhibition is unknown. We show in this study that the F-actin skeleton is essential for FcgammaRIIB-dependent negative regulation. It contains SHIP1, the phosphatase responsible for inhibition, which is constitutively associated with the actin-binding protein, filamin-1. After coaggregation, FcgammaRIIB and FcepsilonRI rapidly interact with the F-actin skeleton and engage SHIP1 and filamin-1. Later, filamin-1 and F-actin dissociate from FcR complexes, whereas SHIP1 remains associated with FcgammaRIIB. Based on these results, we propose a dynamic model in which the submembranous F-actin skeleton forms an inhibitory compartment where filamin-1 functions as a donor of SHIP1 for FcgammaRIIB, which concentrate this phosphatase in the vicinity of FcepsilonRI and thereby extinguish activation signals.

Actins↗
PubMed2006

[The filamin in cell signaling].

This review describes structure and functions of the group of actin-binding proteins--the filamins. Up-to-date facts demonstrate that filamis take part in different regulatory processes in the cell. The filamins have diverse functions--organization of actin polymers into orthogonal networks (three-dimensional scaffolding), attachment of actin filaments to transmembrane receptors, regulation of actin-myosin interaction, regulation of actin assembly. In addition to its main role of the cytoskeleton structural protein, filamin can serve as scaffold protein for formation of signal proteins complexes. One interacts with transcription factors and takes part in signal transduction from cytoplasmic membranes to the nucleus. C-terminal end of filamin interacts with androgen receptor and through cleavage by calpain translocates to the nucleus. Analysis of reviewed experimental dates suggests the conception that intracellular signalization mediated by cytoskeleton proteins is connected with reorganization of the cytoskeleton.

Actins↗
PubMed1977

Interaction of filamin with f-actin in solution.

Filamin is a major high-molecular-weight protein in smooth muscle which was recently identified and isolated [Wang, K., Ash, J. F. & Singer, S. J. (1975) Proc. Natl. Acad. Sci. U.S.A. 72, 4483-4486]. In the present studies, we shown that highly purified chicken gizzard filamin and muscle F-actin react in solution to form aggregates containing both proteins. Occasionally, these aggregates coagulate and contract into a dense gel in the absence of MgATP or CaATP. Immunofluorescence and electron microscopic studies suggest that the F-actin filaments are collected into fiber bundles and a crosslinked fiber meshwork by the binding of filamin molecules. These studies suggest that the function of filamin intact cells may be to regulate the ultrastructural state of F-actin filaments in a variety of dynamic cellular processes.

Actins↗
PubMed1978

Tropomyosin inhibits the interaction of F-actin and filamin.

The value of flow birefringence of F-actin was greatly decreased by filamin due to precipitate formation. This precipitate could be dispersed into birefringent filaments by sonication. Tropomyosin inhibited precipitation of F-actin induced by filamin, and no decrease in birefringence occurred when filamin was added to tropomyosin-bound F-actin. Hence it appears that filamin acts on F-actin in non-muscle cells similarly to alpha-actinin.

Actins↗
PubMed1980

A rapid purification of alpha-actinin, filamin, and a 130,000-dalton protein from smooth muscle.

Brief, low ionic strength extraction of chicken gizzard at 37 degrees C yields a solution containing a limited number of proteins including alpha-actinin, filamin, actin, desmin, and a 130,000-dalton polypeptide. The proteins are then fractionated by Mg2+- and (NH4)2SO4-induced precipitations and by ion exchange and gel filtration column chromatography to give rise to highly purified preparations of alpha-actinin, filamin, and a 130,000-dalton protein. The alpha-actinin and filamin isolated by this scheme are "native" based upon their S20,w values and their ability to bind to F-actin. These procedures, with minor modification, can be used for the purification of alpha-actinin from skeletal muscle and non-muscle tissues as well as for the purification of filamin from non-muscle tissue.

Actinin↗
PubMed1985

The role of actin-binding proteins vinculin, filamin, and fibronectin in intracellular and intercellular linkages in cardiac muscle.

The localization in cardiac muscle and the biochemical properties of fibronectin, filamin, and vinculin were studied. Fibronectin was localized between cardiomyocytes. Filamin was identified in the Z-line region of sarcomers and in the intercalated disks of heart muscle. Vinculin was found to be present in intercalated disks and near the plasma membrane at the cell periphery between external myofibrils and sarcolemma. It was suggested that fibronectin, filamin, and vinculin play an important role in intercellular and intracellular linkages in cardiac muscle.

Cell Communication↗
PubMed2000

Periventricular nodular heterotopia in patients with filamin-1 gene mutations: neuroimaging findings.

BACKGROUND: The filamin-1 (FLN-1) gene is responsible for periventricular nodular heterotopia (PNH), which is an X-linked dominant neuronal migration disorder. OBJECTIVE: To review the clinical and imaging findings in a series of patients with documented filamin-1 mutations. MATERIALS AND METHODS: A retrospective review of the medical records and MR studies of a series of patients with PNH and confirmed FLN-1 mutations was done. There were 16 female patients (age range: .67-71 years; mean = 28.6) with filamin-1 gene mutations. RESULTS: In six of the patients the same mutation was inherited in four generations in one pedigree. In a second pedigree, a distinct mutation was found in two patients in two generations. In a third pedigree, a third mutation was found in four patients in two generations. The remaining four patients had sporadic de novo mutations that were not present in the parents. Ten patients had seizures, and all patients had normal intelligence. In all 16 patients MR demonstrated bilateral near-continuous PNH. There were no consistent radiographic or clinical differences between patients carrying different mutations. CONCLUSION: Patients with confirmed FLN-1 gene mutations are usually female and have a distinctive MR pattern of PNH. Other female patients with this same MR pattern probably harbor FLN-1 mutations and risk transmission to their progeny. This information is important for genetic counseling.

Adolescent↗
PubMed1997

Analysis of the three-dimensional distributions of alpha-actinin, ankyrin, and filamin in developing hearts of normal and cardiac mutant axolotls (Ambystoma mexicanum).

alpha-Actinin is an actin binding protein that assists in the stabilization of the plasma membrane and helps to fix organelles in position in a variety of cell types. In muscle, it is a major component of the Z-lines of organized myofibrils. Ankyrin binds to various elements of the cytoskeletal system including microtubules, microfilaments, and intermediate filaments and may help to anchor these structures to the cell membrane. Filamin is a well-characterized actin-associated protein first isolated from chicken smooth muscle. In addition, filamin is a gel-forming protein which aids in the formation of a loose, yet thick, network of actin filaments. These proteins work together, in conjunction with other cytoskeletal proteins, to permit the contractions of heart muscle cells in vertebrates. In a unique strain of the axolotls (Ambystoma mexicanum) a simple recessive mutation, designated by gene c, results in an incomplete differentiation of the hearts of affected embryos. Although the mutant (c/c) embryos form hearts, they do not beat because of a failure in the formation of organized sarcomeric myofibrils. The current study was undertaken to examine the three-dimensional distributions of three different contractile-cytoskeletal proteins (alpha-actinin, ankyrin, and filamin) during myofibrillogenesis in normal and mutant hearts from early heart-beat stage 37 through advanced embryonic stage 42. Our results demonstrate that the contractile proteins become increasingly better organized in normal hearts as development progresses. In mutant hearts, although the proteins are present in almost normal amounts, they fail to form normally organized myofibrils.

Actinin↗
PubMed1987

A novel 60-kDa smooth muscle protein that binds filamin-actin filament complex.

From the low salt-extracted debris of bovine stomach smooth muscle, a protein having a molecular mass of 60 kDa in SDS-PAGE was newly isolated. Co-sedimentation assay with actin filaments and several actin binding proteins such as filamin, alpha-actinin, caldesmon and fodrin showed that this protein co-sediments with actin only in the presence of filamin. Falling ball viscometric assay showed that this protein increases the viscosity of actin-filamin solution in a dose-dependent manner. Immunoblotting analysis showed specific localization of this protein in smooth and striated muscles.

Actins↗
PubMed2003

Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation.

Cell-extracellular matrix adhesion is an important determinant of cell morphology. We show here that migfilin, a LIM-containing protein, localizes to cell-matrix adhesions, associates with actin filaments, and is essential for cell shape modulation. Migfilin interacts with the cell-matrix adhesion protein Mig-2 (mitogen inducible gene-2), a mammalian homolog of UNC-112, and the actin binding protein filamin through its C- and N-terminal domains, respectively. Loss of Mig-2 or migfilin impairs cell shape modulation. Mig-2 recruits migfilin to cell-matrix adhesions, while the interaction with filamin mediates the association of migfilin with actin filaments. Migfilin therefore functions as an important scaffold at cell-matrix adhesions. Together, Mig-2, migfilin and filamin define a connection between cell matrix adhesions and the actin cytoskeleton and participate in the orchestration of actin assembly and cell shape modulation.

Actin Cytoskeleton↗