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Unleashing formins to remodel the actin and microtubule cytoskeletons

Nature Reviews Molecular Cell Biology volume 11, pages 62–74 (2010)Cite this article

Key Points

  • Formins are a large family of conserved proteins, defined by the presence of formin homology 1 (FH1) and FH2 domains, that directly stimulate actin assembly. Outside of these domains, formins show wide variation in their sequences, which specify key differences in their regulation.

  • Formins promote de novo actin assembly, and their FH2 domains remain processively attached to the elongating end of the filament. Through interactions of their FH1 domains with profilin–actin, formins accelerate, to different degrees, actin addition at filament ends.

  • Recent work has shown that some formins also regulate microtubule dynamics in vivo and in vitro, but the specific mechanistic role of formins in this capacity is yet to be determined.

  • Emerging evidence suggests that formin activities are regulated in vivo at multiple points, including the initial recruitment and activation of formins at membranes, actin nucleation and elongation, and the displacement, inactivation, recycling and turnover of formins.

  • A growing list of formin binding partners has been implicated in the regulation of formin activities, suggesting that multiple signalling pathways converge on formins to trigger cytoskeletal remodelling. Further work is required to elucidate their mechanisms and understand how formins are harnessed to different cellular tasks.

Abstract

Formins are highly conserved proteins that have essential roles in remodelling the actin and microtubule cytoskeletons to influence eukaryotic cell shape and behaviour. Recent work has identified numerous cellular factors that locally recruit, activate or inactivate formins to bridle and unleash their potent effects on actin nucleation and elongation. The effects of formins on microtubules have also begun to be described, which places formins in a prime position to coordinate actin and microtubule dynamics. The emerging complexity in the mechanisms governing formins mirrors the wide range of essential functions that they perform in cell motility, cell division and cell and tissue morphogenesis.

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Figure 1: Cellular structures and functions controlled by formins.
Figure 2: Domain organization of autoinhibited formins.
Figure 3: Proposed model of regulatory points in the formin activity cycle.

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Acknowledgements

We are grateful to J. Moseley, I. Sagot and members of the Goode laboratory for helpful discussions and editing the manuscript, and A. Alberts for sharing information before publication. We apologize to colleagues whose work was not highlighted owing to space limitations. This work was supported in part by grants from the National Institutes of Health to B.G. (GM63691 and GM083137).

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  1. Rosenstiel Basic Medical Science Research Center, Brandeis University, Waltham, 02454, Massachusetts, USA

    Melissa A. Chesarone, Amy Grace DuPage & Bruce L. Goode

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  1. Melissa A. Chesarone
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Glossary

Polyproline tract

A short protein motif, found in many actin regulatory scaffold proteins, that typically contains five or more tandem proline residues and binds profilin or SH3 domains.

Barbed end

The rapidly growing end of an actin filament, so-called because of the arrowhead pattern created when myosin binds. The slowly growing end is called the pointed end.

Microtubule plus end tracking protein

One of a group of proteins that are enriched at the fast growing (plus) ends of microtubules and that influence microtubule dynamics and/or link microtubule plus ends to other cellular structures.

Coiled-coil domain

A structural domain that can mediate protein oligomerization. Coiled coils are helices that are assembled from repeat sequences of seven amino acids (heptads) and twist around each other to form a supercoil.

Armadillo repeat

A folded helical structure encoded by a conserved sequence that was first identified in the D. melanogaster protein Armadillo. This domain is conserved in animals and higher plants and is found in various signalling and cytoskeletal proteins.

PDZ domain

(Postsynaptic-density protein of 95 kDa, Discs large and Zona occludens-1 domain). A protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of the family.

PTEN domain

(Phosphatase and tensin domain). A conserved lipid protein phosphatase domain that has been extensively characterized in the tumour suppressor protein PTEN. Many PTEN domain-containing proteins regulate cytoskeletal organization.

Total internal reflection fluorescence microscopy

A microscopy technique that enables the real-time visualization of fluorescently labelled molecules in a thin region of a specimen, greatly reducing background, and that has enabled actin dynamics to be studied at the single filament level.

F-actin

(Filamentous actin). A flexible, helical polymer of globular actin (G-actin) subunits, with a diameter of 5–9 nm.

Capping protein

One of a group of ubiquitously expressed proteins that are found in eukaryotic cells and show high affinity for the barbed ends of actin filaments, thereby antagonizing filament growth.

ENA/VASP

(Enabled/vasodilator-stimulated phosphoprotein). A member of a family of actin-binding proteins that are required for many cellular processes, including motility. Similar to formins, ENA/VASP proteins associate with the barbed ends of actin filaments and protect growing filaments from capping proteins, although they appear to use a distinct mechanism.

Kinetochore

A large multiprotein complex that assembles onto the centromeric DNA of chromosomes and links the chromosome to microtubule plus ends in the mitotic spindle. It plays an instrumental role in chromosome segregation during mitosis.

Microtubule array

A spatial arrangement of microtubule polymers harnessed to cellular tasks that include mitosis, intracellular transport and directional cell movement.

Amphipathic helix

A helical structure that consists of hydrophobic non-polar residues on one side and hydrophilic polar residues on the other side.

Rho GTPase

One of a conserved family of small enzymes that converts GTP to GDP and acts as a 'molecular switch' that is active in the GTP-bound form and inactive in the GDP-bound form. Active Rho proteins bind to effectors, such as formins, to trigger cytoskeletal remodelling.

Farnesylation

A post-translational modification in which a farnesyl group (a hydrophobic group of three isoprene units) is conjugated to proteins, such as Ras GTPases, that contain a C-terminal CAAX motif. Farnesylation promotes insertion of the modified proteins into lipid bilayers.

Phagocytic cup

An actin-rich, cup-like extension of the peripheral membrane that partially encircles foreign particles or bacteria during the early stages of the phagocytic process.

WAVE complex

(WASP-family verprolin-homologous protein complex). A complex of five proteins that regulates Arp2/3 complex-mediated actin assembly. The defining member of this complex, WAVE, is related to WASP and directly stimulates the Arp2/3 complex to nucleate actin assembly, while other components of the complex regulate WAVE.

Adherens junction

A cell–cell adhesion complex that contains classical cadherins and catenins, which are attached to cytoplasmic actin filaments.

α-catenin

A central component of adherens junctions that links cell adhesion molecules, such as cadherin, to actin filaments.

Tropomyosin

One of a conserved family of actin binding proteins that bind to the sides of actin filaments, stabilizing actin, and in some cases binds to formins to promote actin assembly.

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Chesarone, M., DuPage, A. & Goode, B. Unleashing formins to remodel the actin and microtubule cytoskeletons. Nat Rev Mol Cell Biol 11, 62–74 (2010). https://doi.org/10.1038/nrm2816

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