Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The many faces of filamin: A versatile molecular scaffold for cell motility and signalling

Abstract

Filamins were discovered as the first family of non-muscle actin-binding protein. They are lage cytoplasmic proteins that cross-link cortical actin into a dynamic three-dimensional structure. Filamins have also been reported to interact with a large number of cellular proteins of great functional diversity, suggesting that they are unusually versatile signalling scaffolds. More recently, genetic mutations in filamin A and B have been reported to cause a wide range of human diseases, suggesting that different diseases highlight distinct filamin interactions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of filamin's molecular interactions.
Figure 2: Periventricular heterotopia.
Figure 3: FLNA mutations identified in various human genetic disorders.

Similar content being viewed by others

References

  1. Hartwig, J. H. & Stossel, T. P. Isolation and properties of actin, myosin, and a new actinbinding protein in rabbit alveolar macrophages. J. Biol. Chem. 250, 5696–5705 (1975).

    CAS  PubMed  Google Scholar 

  2. Wang, K., Ash, J. F. & Singer, S. J. Filamin, a new high-molecular-weight protein found in smooth muscle and non-muscle cells. Proc. Natl Acad. Sci. USA 72, 4483–4486 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gorlin, J. B. et al. Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring. J. Cell Biol. 111, 1089–1105 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Weihing, R. R. Actin-binding and dimerization domains of HeLa cell filamin. Biochemistry 27, 1865–1869 (1988).

    Article  CAS  PubMed  Google Scholar 

  5. Stossel, T. P. & Hartwig, J. H. Interactions between actin, myosin, and an actin-binding protein from rabbit alveolar macrophages. Alveolar macrophage myosin Mg2+-adenosine triphosphatase requires a cofactor for activation by actin. J. Biol. Chem. 250, 5706–5712 (1975).

    CAS  PubMed  Google Scholar 

  6. Brotschi, E. A., Hartwig, J. H. & Stossel, T. P. The gelation of actin by actin-binding protein. J. Biol. Chem. 253, 8988–8993 (1978).

    CAS  PubMed  Google Scholar 

  7. Janmey, P. A., Hvidt, S., Lamb, J. & Stossel, T. P. Resemblance of actin-binding protein/actin gels to covalently crosslinked networks. Nature 345, 89–92 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Stendahl, O. I., Hartwig, J. H., Brotschi, E. A. & Stossel, T. P. Distribution of actin-binding protein and myosin in macrophages during spreading and phagocytosis. J. Cell Biol. 84, 215–224 (1980).

    Article  CAS  PubMed  Google Scholar 

  9. Weihing, R. R. The filamins: properties and functions. Can. J. Biochem. Cell Biol. 63, 397–413 (1985).

    Article  CAS  PubMed  Google Scholar 

  10. Stossel, T. P. et al. Filamins as integrators of cell mechanics and signalling. Nature Rev. Mol. Cell. Biol. 2, 138–145 (2001).

    Article  CAS  Google Scholar 

  11. Thompson, T. G. et al. Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein. J. Cell Biol. 148, 115–126 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sheen, V. L. et al. Filamin A and Filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact. Hum. Mol. Genet. 11, 2845–2854 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Takafuta, T., Wu, G., Murphy, G. F. & Shapiro, S. S. Human α-filamin is a new protein that interacts with the cytoplasmic tail of glycoprotein Ibalpha. J. Biol. Chem. 273, 17531–17538 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. van der Flier, A. & Sonnenberg, A. Structural and functional aspects of filamins. Biochim. Biophys. Acta 1538, 99–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Huttenlocher, P. R., Taravath, S. & Mojtahedi, S. Periventricular heterotopia and epilepsy. Neurology 44, 51–55 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Eksioglu, Y. Z. et al. Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron 16, 77–87 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Kakita, A. et al. Bilateral periventricular nodular heterotopia due to filamin 1 gene mutation: widespread glomeruloid microvascular anomaly and dysplastic cytoarchitecture in the cerebral cortex. Acta Neuropathol. (Berl.) 104, 649–657 (2002).

    CAS  Google Scholar 

  18. Fox, J. W. et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 21, 1315–1325 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Sheen, V. L. et al. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum. Mol. Genet. 10, 1775–1783 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Guerrini, R. et al. Germline and mosaic mutations of FLN1 in men with periventricular heterotopia. Neurology 63, 51–56 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Thomas, P. et al. Ehlers-Danlos syndrome with subependymal periventricular heterotopias. Neurology 46, 1165–1167 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Moro, F. et al. Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene. Neurology 58, 916–921 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Sharma, C. P., Ezzell, R. M. & Arnaout, M. A. Direct interaction of filamin (ABP-280) with the β 2-integrin subunit CD18. J. Immunol. 154, 3461–3470 (1995).

    CAS  PubMed  Google Scholar 

  24. Calderwood, D. A. et al. Increased filamin binding to β-integrin cytoplasmic domains inhibits cell migration. Nature Cell Biol. 3, 1060–1068 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Ohta, Y., Suzuki, N., Nakamura, S., Hartwig, J. H. & Stossel, T. P. The small GTPase RalA targets filamin to induce filopodia. Proc. Natl Acad. Sci. USA 96, 2122–2128 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Marti, A. et al. Actin-binding protein-280 binds the stress-activated protein kinase (SAPK) activator SEK-1 and is required for tumor necrosis factor-α activation of SAPK in melanoma cells. J. Biol. Chem. 272, 2620–2628 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Sasaki, A., Masuda, Y., Ohta, Y., Ikeda, K. & Watanabe, K. Filamin associates with Smads and regulates transforming growth factor-β signaling. J. Biol. Chem. 276, 17871–17877 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Robertson, S. P. et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nature Genet. 33, 487–491 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Dudding, B. A., Gorlin, R. J. & Langer, L. O. The oto-palato-digital syndrome. A new symptom-complex consisting of deafness, dwarfism, cleft palate, characteristic facies, and a generalized bone dysplasia. Am. J. Dis. Child. 113, 214–221 (1967).

    Article  CAS  PubMed  Google Scholar 

  30. Stratton, R. F. & Bluestone, D. L. Oto-palatal-digital syndrome type II with X-linked cerebellar hypoplasia/hydrocephalus. Am. J. Med. Genet. 41, 169–172 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Stoll, C. & Alembik, Y. Oto-palato-digital syndrome type II. Genet. Couns. 5, 61–66 (1994).

    CAS  PubMed  Google Scholar 

  32. Gorlin, R. J. & Cohen, M. M. Jr. Frontometaphyseal dysplasia. A new syndrome. Am. J. Dis. Child. 118, 487–494 (1969).

    Article  CAS  PubMed  Google Scholar 

  33. Coste, F., Maroteaux, P. & Chouraki, L. Osteodysplasty (Melnick and Needles syndrome). Report of a case. Ann. Rheum. Dis. 27, 360–366 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gorlin, R. J. & Langer, L. O. Jr. Melnick-Needles syndrome: radiographic alterations in the mandible. Radiology 128, 351–353 (1978).

    Article  CAS  PubMed  Google Scholar 

  35. Neou, P., Kyrkanides, S., Gioureli, E. & Bartsocas, C. S. Melnick-Needles syndrome in a mother and her son. Genet. Couns. 7, 123–129 (1996).

    CAS  PubMed  Google Scholar 

  36. Zenker, M. et al. A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts. Am. J. Hum. Genet. 74, 731–737 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kaplan, J. M. et al. Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nature Genet. 24, 251–256 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Krakow, D. et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nature Genet. 36, 405–410 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christopher A. Walsh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Feng, Y., Walsh, C. The many faces of filamin: A versatile molecular scaffold for cell motility and signalling. Nat Cell Biol 6, 1034–1038 (2004). https://doi.org/10.1038/ncb1104-1034

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1104-1034

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing