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Nucleating actin for invasion

Key Points

  • Actin polymerization inside cells is initiated by actin nucleation factors. Reassembly of the actin cytoskeleton is essential for invasive cell migration. Understanding the specific mechanisms of action and regulation of the diverse and growing number of actin nucleators is likely to provide new ideas for developing treatments that inhibit cancer spread and inflammatory conditions.

  • Actin nucleators such as formins or the Arp2/3 complex and nucleation-promoting factors have numerous and diverse functions in invasive cancer cell migration, including the formation of protrusive structures, assembly of cell–cell contacts and matrix degradation. In addition, they have been implicated in the regulation of proinvasive signalling pathways.

  • There is now a large body of clinical evidence for specific roles of actin nucleators in cancer progression. Importantly, many of these factors seem to be associated with advanced disease and the metastatic spread of human cancers.

  • Actin nucleation factors now emerge as promising targets for therapeutic intervention in metastatic and invasive or inflammatory diseases. The first small-molecule inhibitors of actin nucleators have been reported very recently.

Abstract

The invasion of cancer cells into the surrounding tissue is a prerequisite and initial step in metastasis, which is the leading cause of death from cancer. Invasive cell migration requires the formation of various structures, such as invadopodia and pseudopodia, which require actin assembly that is regulated by specialized actin nucleation factors. There is a large variety of different actin nucleators in human cells, such as formins, spire and Arp2/3-regulating proteins, and the list is likely to grow. Studies of the mechanisms of various actin nucleation factors that are involved in cancer cell function may ultimately provide new treatments for invasive and metastatic disease.

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Figure 1: Actin nucleation and turnover.
Figure 2: Typical protrusive structures in invasive cancer cells.
Figure 3: Actin nucleation factors in transcriptional regulation.
Figure 4: Scheme of Arp2/3 complex interaction with an actin nucleus.

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Acknowledgements

The authors are grateful to B. Di Ventura and H. Morrison for comments on the manuscript and to laboratory members for helpful discussions. T.K. is a recipient of a DFG fellowship (KI 1605/1-1). R.G. is supported by grants from the DFG (GR 2111/2-1), Deutsche Krebshilfe e.V. (108293) and the LOEWE program Tumour & Inflammation.

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Glossary

Structurally polarized filaments

Actin filaments are structurally polarized owing to uniform orientation of asymmetric subunits. As a result, polarized filaments have two ends, a plus and a minus end, which differ in their biochemical properties.

Capping proteins

Ubiquitously expressed proteins that are able to bind to either the plus or the minus end of actin filaments, thereby preventing both association and dissociation of actin monomers.

Profilin–actin

A complex of ATP-actin and profilin, an abundantly expressed actin monomer-binding protein. Profilin–actin complexes can bind to formins and Ena/VASP proteins, thereby delivering actin monomers for incorporation into a growing actin filament.

Choroidal

A middle layer of the eye surface located between sclera and retina.

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Nürnberg, A., Kitzing, T. & Grosse, R. Nucleating actin for invasion. Nat Rev Cancer 11, 177–187 (2011). https://doi.org/10.1038/nrc3003

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