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Filamins as integrators of cell mechanics and signalling

Nature Reviews Molecular Cell Biology volume 2, pages 138–145 (2001)Cite this article

Key Points

  • Molecules that crosslink actin filaments into particular architectures are important components of cell structure and movement. Filamins are one of the first of such components recognized and are among the most important.

  • Filamins are extended dimers composed of subunits that contain characteristic β-pleated sheet repeats. Vertebrate filamins have amino-terminal actin-binding domains and self-associate at the carboxyl termini of their subunits.

  • The main human filamin (filamin A) is encoded on the X chromosome. A second filamin gene (filamin B) is encoded on chromosome 3 and a muscle-specific filamin gene (filamin C) is encoded on chromosome 7.

  • So far two filamin genes have been recognized in Drosophila. Dictyostelium amoebae have only one filamin species which is truncated compared with vertebrate and Drosophila filamins.

  • Filamins cause actin filaments to branch with high angles leading efficiently to the formation of actin gels in vitro. The filamins reside at branches between orthogonally intersecting filaments in the peripheral cytoplasm of cells.

  • Filamins also bind over 20 diverse cellular proteins, including membrane receptors and intracellular signalling macromolecules.

  • Cells missing the main filamins have defects in surface stability and locomotion and in some of the functions ascribed to the filamin binding partners. A mutation in the filamin A gene is lethal for males and the cause of periventricular heterotopia in females chimeric for the mutation.

Abstract

Filamins are large actin-binding proteins that stabilize delicate three-dimensional actin webs and link them to cellular membranes. They integrate cellular architectural and signalling functions and are essential for fetal development and cell locomotion. Here, we describe the history, structure and function of this group of proteins.

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Figure 1: The structure of human FLNa.
Figure 2: Schematic subunit structures of some filamins.
Figure 3: Electron micrographs showing crosslinked complexes of actin filaments.
Figure 4: Electron micrograph of the actin cytoskeleton at the periphery of a human blood platelet.
Figure 5: Possible organization of FLNa at the surface of a human blood platelet.

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Acknowledgements

Some of the research reported in this review was supported by the NIH grants and by the Edwin S Webster Foundation (to T.P.S and J.H.H). We appreciate comments on this paper by Kuan Wang, NIAMS, NIH, who with S. John Singer was the first to purify avian gizzard filamin.

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Authors and Affiliations

  1. Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA

    Thomas P. Stossel & John H. Hartwig

  2. Albert Einstein College of Medicine, New York, 10461, New York, USA

    John Condeelis

  3. Yale Medical School, New Haven, 06520, Connecticut, USA

    Lynn Cooley

  4. University of Cologne, Cologne, D-50931, Germany

    Angelika Noegel

  5. Ludwig-Maximilians University, Munich, D-80336, Germany

    Michael Schleicher

  6. Jefferson Medical College, Philadelphia , 19107, Pennsylvania, USA

    Sandor S. Shapiro

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Movie. Morphology of FLNa-repleted cells (left) derived from FLNa-null M2 cells (right). Filamin-expressing cells ruffle and begin to translocate, whereas M2 cells remain stationary and bleb.

Supplementary information

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DATABASE LINKS

filamin

cheerio

β-spectrin

dystrophin

α-actinin

calponin

utrophin

Arp2/3 complex

Ral

Cdc42

RhoA

Rac1

Trio

β1 integrin

protein kinase A

protein kinase C

Ca2+/calmodulin-dependent protein kinase II

p90 ribosomal S6 kinase

human periventricular heterotopia

FURTHER INFORMATION

Stossel lab page

ENCYCLOPEDIA OF LIFE SCIENCES

Actin and actin filaments

Glossary

PHAGOCYTOSIS

Actin-dependent process, by which cells engulf external particulate material by extension and fusion of pseudopods.

OSMOTIC FLUID FLOW

The movement of fluid across semi-permeable membranes from lesser to greater solute concentrations.

HYDROSTATIC FLUID FLOW

The movement of fluid under mechanical pressure in the direction of least resistance.

MACROPHAGE

Any cell of the mononuclear phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.

FIBROBLAST

Common cell type found in connective tissue in many parts of the body, which secretes an extracellular matrix rich in collagen and other macromolecules.

PARALOGUE

Gene products on opposite branches of a duplicated gene family. Orthologues are on the same branch (for example, FLNa, FLNb and FLNc). Paralogues and orthologues are homologues.

OVARIAN RING CANAL

In Drosophila, a single oocyte develops in egg chambers containing 15 nurse cells connected by intercellular bridges ? the ring canals.

GEL

A liquid becomes a gel when a 'giant molecule' occupies the entire liquid.

POINTED END

Defined by arrowhead appearance of myosin head fragments bound to the actin filaments.

LEADING EDGE

The thin margin of a lamellipodium spanning the area of the cell from the plasma membrane to about 1 μm back into the lamellipodium.

PLATELETS

The smallest blood cells, which are important in haemostasis and blood coagulation.

MELANOMA

Cancer derived from melanocytes, the cells that synthesize melanin pigments.

RHO FAMILY GTPASES

Ras-related GTPases involved in controlling the polymerization of actin.

DICTYOSTELIUM SLUGS

Aggregated form of Dictyostelium amoebae.

CALPAIN

Calcium-dependent cysteine proteases involved in signal transduction in a variety of cellular processes.

LAMELLA

Flat, sheet-like protrusions at the edge of the cell. A fan-shaped lamella is a prominent feature identifying the leading edge of a cell undergoing locomotion on a flat surface. Actin networks are the principal structures within these lamellae.

EPILEPTIC SEIZURE

Commonly known as fits, seizures are the result of uncontrolled bursts of neuronal activation in the brain that usually lead to repetitive motor activity, such as shaking of extremities. Epilepsy is the term applied to recurrent seizures. Anatomical malformations, tumours, scars, infection, inflammation, haemorrhage and metabolic derangements can cause seizures.

LATERAL VENTRICLES

Cavernous structures in the middle of the cerebrum that contain cerebrospinal fluid.

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Stossel, T., Condeelis, J., Cooley, L. et al. Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol 2, 138–145 (2001). https://doi.org/10.1038/35052082

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