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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Cav2.2-NFAT2-USP43 axis promotes invadopodia formation and breast cancer metastasis through cortactin stabilization
Cell Death & Disease Open Access 22 September 2022
Nature Communications Open Access 28 March 2022
Cellular Oncology Open Access 28 September 2021
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Weigelt, B., Peterse, J. L. & van 't Veer, L. J. Breast cancer metastasis: markers and models. Nature Rev. Cancer 5, 591–602 (2005).
Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nature Rev. Cancer 9, 274–284 (2009).
Yilmaz, M. & Christofori, G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28, 15–33 (2009).
Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).
Wolf, K. et al. Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 160, 267–277 (2003).
Sahai, E. & Marshall, C. J. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nature Cell Biol. 5, 711–719 (2003).
Sabeh, F., Shimizu-Hirota, R. & Weiss, S. J. Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited. J. Cell Biol. 185, 11–19 (2009).
Sanz-Moreno, V. & Marshall, C. J. The plasticity of cytoskeletal dynamics underlying neoplastic cell migration. Curr. Opin. Cell Biol. 22, 690–696 (2010).
Chesarone, M. A. & Goode, B. L. Actin nucleation and elongation factors: mechanisms and interplay. Curr. Opin. Cell Biol. 21, 28–37 (2009).
Campellone, K. G. & Welch, M. D. A nucleator arms race: cellular control of actin assembly. Nature Rev. Mol. Cell Biol. 11, 237–251 (2010).
Ellenbroek, S. I. & Collard, J. G. Rho GTPases: functions and association with cancer. Clin. Exp. Metastasis 24, 657–672 (2007).
Sahai, E. & Marshall, C. J. RHO-GTPases and cancer. Nature Rev. Cancer 2, 133–142 (2002).
Wang, W., Eddy, R. & Condeelis, J. The cofilin pathway in breast cancer invasion and metastasis. Nature Rev. Cancer 7, 429–440 (2007).
Bugyi, B. & Carlier, M. F. Control of actin filament treadmilling in cell motility. Annu. Rev. Biophys. 39, 449–470 (2010).
Holmes, K. C., Popp, D., Gebhard, W. & Kabsch, W. Atomic model of the actin filament. Nature 347, 44–49 (1990).
Pollard, T. D. & Cooper, J. A. Actin, a central player in cell shape and movement. Science 326, 1208–1212 (2009).
dos Remedios, C. G. et al. Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol. Rev. 83, 433–473 (2003).
Le Clainche, C. & Carlier, M. F. Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol. Rev. 88, 489–513 (2008).
Heasman, S. J. & Ridley, A. J. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nature Rev. Mol. Cell Biol. 9, 690–701 (2008).
Higgs, H. N. & Peterson, K. J. Phylogenetic analysis of the formin homology 2 domain. Mol. Biol. Cell 16, 1–13 (2005).
Baarlink, C., Brandt, D. & Grosse, R. SnapShot: Formins. Cell 142, 172, 172 e1 (2010).
Pruyne, D. et al. Role of formins in actin assembly: nucleation and barbed-end association. Science 297, 612–615 (2002).
Sagot, I., Rodal, A. A., Moseley, J., Goode, B. L. & Pellman, D. An actin nucleation mechanism mediated by Bni1 and Profilin. Nature Cell Biol. 4, 626–631 (2002).
Kovar, D. R. Molecular details of formin-mediated actin assembly. Curr. Opin. Cell Biol. 18, 11–17 (2006).
Goode, B. L. & Eck, M. J. Mechanism and function of formins in the control of actin assembly. Annu. Rev. Biochem. 76, 593–627 (2007).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).
Narumiya, S., Tanji, M. & Ishizaki, T. Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev. 28, 65–76 (2009).
DeWard, A. D., Eisenmann, K. M., Matheson, S. F. & Alberts, A. S. The role of formins in human disease. Biochim. Biophys. Acta 1803, 226–233 (2010).
Kitzing, T. M. et al. Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. Genes Dev. 21, 1478–1483 (2007).
Lizarraga, F. et al. Diaphanous-related formins are required for invadopodia formation and invasion of breast tumor cells. Cancer Res. 69, 2792–2800 (2009).
Holeiter, G. et al. Deleted in liver cancer 1 controls cell migration through a Dia1-dependent signaling pathway. Cancer Res. 68, 8743–8751 (2008).
Tanji, M. et al. mDia1 targets v-Src to the cell periphery and facilitates cell transformation, tumorigenesis, and invasion. Mol. Cell Biol. 30, 4604–4615 (2010).
Shi, Y. et al. The mDial formin is required for neutrophil polarization, migration, and activation of the LARG/RhoA/ROCK signaling axis during chemotaxis. J. Immunol. 182, 3837–3845 (2009).
Hannemann, S. et al. The Diaphanous-related Formin FHOD1 associates with ROCK1 and promotes Src-dependent plasma membrane blebbing. J. Biol. Chem. 283, 27891–27903 (2008).
Han, Y. et al. Formin-like 1 (FMNL1) is regulated by N-terminal myristoylation and induces polarized membrane blebbing. J. Biol. Chem. 284, 33409–33417 (2009).
Di Vizio, D. et al. Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease. Cancer Res. 69, 5601–5609 (2009). This intruiging study shows that genetic loss of the formin DIAPH3 is associated with prostate cancer metastasis, possibly through increased plasma membrane blebbing and oncosome production.
Eisenmann, K. M. et al. Dia-interacting protein modulates formin-mediated actin assembly at the cell cortex. Curr. Biol. 17, 579–591 (2007).
Favaro, P. M. B. et al. High expression of FMNL1 protein in T non-Hodgkin's lymphomas. Leukemia Research 30, 735–738 (2006).
Schuster, I. G. et al. Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies. Blood 110, 2931–2939 (2007). A very interesting paper describing presentation of a formin-derived antigenic epitop that can activate T cell clones to target lymphoma.
Zhu, X.-L., Liang, L. & Ding, Y.-Q. Overexpression of FMNL2 is closely related to metastasis of colorectal cancer. Intern. J. Colorectal Dis. 23, 1041–1047 (2008).
Kitzing, T. M., Wang, Y., Pertz, O., Copeland, J. W. & Grosse, R. Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC. Oncogene 29, 2441–2448 (2010). The first comprehensive formin screen on differently invading cancer cell types, which identified a RhoC–FMNL2 module for rounded invasion.
Olson, E. N. & Nordheim, A. Linking actin dynamics and gene transcription to drive cellular motile functions. Nature Rev. Mol. Cell Biol. 11, 353–365 (2010).
Medjkane, S., Perez-Sanchez, C., Gaggioli, C., Sahai, E. & Treisman, R. Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and experimental metastasis. Nature Cell Biol. 11, 257–268 (2009).
Brandt, D. T. et al. SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of β1-integrin. Nature Cell Biol. 11, 557–568 (2009).
Mullins, R. D., Heuser, J. A. & Pollard, T. D. The interaction of Arp2/3 complex with actin: nucleation, high affinity pointed end capping, and formation of branching networks of filaments. Proc. Natl Acad. Sci. USA 95, 6181–6186 (1998).
Pantaloni, D., Boujemaa, R., Didry, D., Gounon, P. & Carlier, M. F. The Arp2/3 complex branches filament barbed ends: functional antagonism with capping proteins. Nature Cell Biol. 2, 385–391 (2000).
Goley, E. D. et al. An actin-filament-binding interface on the Arp2/3 complex is critical for nucleation and branch stability. Proc. Natl Acad. Sci. USA 107, 8159–8164 (2010).
Urban, E., Jacob, S., Nemethova, M., Resch, G. P. & Small, J. V. Electron. tomography reveals unbranched networks of actin filaments in lamellipodia. Nature Cell Biol. 12, 429–435 (2010).
Lai, F. P. et al. Arp2/3 complex interactions and actin network turnover in lamellipodia. EMBO J. 27, 982–992 (2008).
Rouiller, I. et al. The structural basis of actin filament branching by the Arp2/3 complex. J. Cell Biol. 180, 887–895 (2008).
Sarmiento, C. et al. WASP family members and formin proteins coordinate regulation of cell protrusions in carcinoma cells. J. Cell Biol. 180, 1245–1260 (2008).
Yamaguchi, H. et al. Molecular mechanisms of invadopodium formation: the role of the N-WASP–Arp2/3 complex pathway and cofilin. J. Cell Biol. 168, 441–452 (2005).
Wang, W. et al. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62, 6278–6288 (2002).
Wang, W. et al. Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res. 64, 8585–8594 (2004).
Wang, W. et al. Coordinated regulation of pathways for enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors. Cancer Res. 67, 3505–3511 (2007). References 55 and 56 examine the change of gene expression in invading tumour cells collected in vivo and further highlight the role of the Arp2/3 complex downstream of the EGF receptor.
Otsubo, T. et al. Involvement of Arp2/3 complex in the process of colorectal carcinogenesis. Mod. Pathol. 17, 461–467 (2004).
Laurila, E., Savinainen, K., Kuuselo, R., Karhu, R. & Kallioniemi, A. Characterization of the 7q21-q22 amplicon identifies ARPC1A, a subunit of the Arp2/3 complex, as a regulator of cell migration and invasion in pancreatic cancer. Genes Chromosom. Cancer 48, 330–339 (2009).
Kumagai, K. et al. Arpc1b gene is a candidate prediction marker for choroidal malignant melanomas sensitive to radiotherapy. Invest. Ophthalmol. Vis. Sci. 47, 2300–2304 (2006).
Molli, P. R. et al. Arpc1b, a centrosomal protein, is both an activator and substrate of Aurora, A. J. Cell Biol. 190, 101–114 (2010).
Wu, H., Reynolds, A. B., Kanner, S. B., Vines, R. R. & Parsons, J. T. Identification and characterization of a novel cytoskeleton-associated pp60src substrate. Mol. Cell Biol. 11, 5113–5124 (1991).
Martinez-Quiles, N., Ho, H. Y., Kirschner, M. W., Ramesh, N. & Geha, R. S. Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Mol. Cell Biol. 24, 5269–5280 (2004).
Tehrani, S., Tomasevic, N., Weed, S., Sakowicz, R. & Cooper, J. A. Src phosphorylation of cortactin enhances actin assembly. Proc. Natl Acad. Sci. USA 104, 11933–11938 (2007).
Kowalski, J. R. et al. Cortactin regulates cell migration through activation of N-WASP. J. Cell Sci. 118, 79–87 (2005).
Uruno, T., Liu, J., Li, Y., Smith, N. & Zhan, X. Sequential interaction of actin-related proteins 2 and 3 (Arp2/3) complex with neural Wiscott-Aldrich syndrome protein (N-WASP) and cortactin during branched actin filament network formation. J. Biol. Chem. 278, 26086–26093 (2003).
Desmarais, V. et al. N-WASP and cortactin are involved in invadopodium-dependent chemotaxis to EGF in breast tumor cells. Cell. Motil. Cytoskeleton 66, 303–316 (2009).
Artym, V. V., Zhang, Y., Seillier-Moiseiwitsch, F., Yamada, K. M. & Mueller, S. C. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Res. 66, 3034–3043 (2006).
Oser, M. et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J. Cell Biol. 186, 571–587 (2009).
Bowden, E. T., Barth, M., Thomas, D., Glazer, R. I. & Mueller, S. C. An invasion-related complex of cortactin, paxillin and PKCmu associates with invadopodia at sites of extracellular matrix degradation. Oncogene 18, 4440–4449 (1999).
Lorenz, M., Yamaguchi, H., Wang, Y., Singer, R. H. & Condeelis, J. Imaging sites of N-wasp activity in lamellipodia and invadopodia of carcinoma cells. Curr. Biol. 14, 697–703 (2004).
Mizutani, K., Miki, H., He, H., Maruta, H. & Takenawa, T. Essential role of neural Wiskott-Aldrich syndrome protein in podosome formation and degradation of extracellular matrix in src-transformed fibroblasts. Cancer Res. 62, 669–674 (2002).
Bryce, N. S. et al. Cortactin promotes cell motility by enhancing lamellipodial persistence. Curr. Biol. 15, 1276–1285 (2005).
Clark, E. S., Whigham, A. S., Yarbrough, W. G. & Weaver, A. M. Cortactin is an essential regulator of matrix metalloproteinase secretion and extracellular matrix degradation in invadopodia. Cancer Res. 67, 4227–4235 (2007).
Sossey-Alaoui, K., Ranalli, T. A., Li, X., Bakin, A. V. & Cowell, J. K. WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression. Exp. Cell Res. 308, 135–145 (2005).
Ayala, I. et al. Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation. J. Cell Sci. 121, 369–378 (2008).
Fernando, H. S., Sanders, A. J., Kynaston, H. G. & Jiang, W. G. WAVE1 is associated with invasiveness and growth of prostate cancer cells. J. Urol. 180, 1515–1521 (2008).
Fernando, H. S., Sanders, A. J., Kynaston, H. G. & Jiang, W. G. WAVE3 is associated with invasiveness in prostate cancer cells. Urol. Oncol. 28, 320–327 (2010).
Sossey-Alaoui, K. et al. Down-regulation of WAVE3, a metastasis promoter gene, inhibits invasion and metastasis of breast cancer cells. Am. J. Pathol. 170, 2112–2121 (2007).
Kurisu, S., Suetsugu, S., Yamazaki, D., Yamaguchi, H. & Takenawa, T. Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells. Oncogene 24, 1309–1319 (2005).
Iwaya, K. et al. Correlation between liver metastasis of the colocalization of actin-related protein 2 and 3 complex and WAVE2 in colorectal carcinoma. Cancer Sci. 98, 992–999 (2007).
Iwaya, K., Norio, K. & Mukai, K. Coexpression of Arp2 and WAVE2 predicts poor outcome in invasive breast carcinoma. Mod. Pathol. 20, 339–343 (2007).
Fernando, H. S. et al. Expression of the WASP verprolin-homologues (WAVE members) in human breast cancer. Oncology 73, 376–383 (2007).
Yanagawa, R. et al. Genome-wide screening of genes showing altered expression in liver metastases of human colorectal cancers by cDNA microarray. Neoplasia 3, 395–401 (2001).
Wang, W. S. et al. The expression of CFL1 and N-WASP in esophageal squamous cell carcinoma and its correlation with clinicopathological features. Dis. Esophagus 23, 512–521 (2010).
Rothschild, B. L. et al. Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification. Cancer Res. 66, 8017–8025 (2006).
Buday, L. & Downward, J. Roles of cortactin in tumor pathogenesis. Biochim. Biophys. Acta 1775, 263–273 (2007).
Weaver, A. M. Cortactin in tumor invasiveness. Cancer Lett. 265, 157–166 (2008).
Hofman, P. et al. Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status. Br. J. Cancer 98, 956–964 (2008).
Zhang, L. H. et al. Dominant expression of 85-kDa form of cortactin in colorectal cancer. J. Cancer Res. Clin. Oncol. 132, 113–120 (2006).
Clark, E. S. et al. Aggressiveness of HNSCC tumors depends on expression levels of cortactin, a gene in the 11q13 amplicon. Oncogene 28, 431–444 (2009).
Chuma, M. et al. Overexpression of cortactin is involved in motility and metastasis of hepatocellular carcinoma. J. Hepatol 41, 629–636 (2004).
Luo, M. L. et al. Amplification and overexpression of CTTN (EMS1) contribute to the metastasis of esophageal squamous cell carcinoma by promoting cell migration and anoikis resistance. Cancer Res. 66, 11690–11699 (2006).
Li, Y. et al. Cortactin potentiates bone metastasis of breast cancer cells. Cancer Res. 61, 6906–6911 (2001). This study demonstrates that cancer cells overexpressing cortactin show a higher frequency for metastasis in nude mice, which depends on tyrosine phosphorylation of cortactin.
Ammer, A. G. et al. Saracatinib impairs head and neck squamous cell carcinoma invasion by disrupting invadopodia function. J. Cancer Sci. Ther. 1, 52–61 (2009).
Timpson, P. et al. Aberrant expression of cortactin in head and neck squamous cell carcinoma cells is associated with enhanced cell proliferation and resistance to the epidermal growth factor receptor inhibitor gefitinib. Cancer Res. 67, 9304–9314 (2007). An intriguing report demonstrating that cortactin promotes resistance to an anticancer drug gefitinib.
Timpson, P., Lynch, D. K., Schramek, D., Walker, F. & Daly, R. J. Cortactin overexpression inhibits ligand-induced down-regulation of the epidermal growth factor receptor. Cancer Res. 65, 3273–3280 (2005).
Sanz-Moreno, V. et al. Rac activation and inactivation control plasticity of tumor cell movement. Cell 135, 510–523 (2008). This elegant paper identifies Rac-regulated WAVE2 function as a key mediator for tumour cell plasticity from amoeboid to mesenchymal invasion.
Yamazaki, D., Kurisu, S. & Takenawa, T. Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates. Oncogene 28, 1570–1583 (2009).
Gadea, G., Sanz-Moreno, V., Self, A., Godi, A. & Marshall, C. J. DOCK10-mediated Cdc42 activation is necessary for amoeboid invasion of melanoma cells. Curr. Biol. 18, 1456–1465 (2008).
Sossey-Alaoui, K., Bialkowska, K. & Plow, E. F. The miR200 family of microRNAs regulates WAVE3-dependent cancer cell invasion. J. Biol. Chem. 284, 33019–33029 (2009).
Beli, P., Mascheroni, D., Xu, D. & Innocenti, M. WAVE and Arp2/3 jointly inhibit filopodium formation by entering into a complex with mDia2. Nature Cell Biol. 10, 849–857 (2008).
Silva, J. M. et al. Cyfip1 is a putative invasion suppressor in epithelial cancers. Cell 137, 1047–1061 (2009).
Bourguignon, L. Y., Peyrollier, K., Gilad, E. & Brightman, A. Hyaluronan-CD44 interaction with neural Wiskott-Aldrich syndrome protein (N-WASP) promotes actin polymerization and ErbB2 activation leading to beta-catenin nuclear translocation, transcriptional up-regulation, and cell migration in ovarian tumor cells. J. Biol. Chem. 282, 1265–1280 (2007).
Lyubimova, A. et al. Neural Wiskott-Aldrich syndrome protein modulates Wnt signaling and is required for hair follicle cycling in mice. J. Clin. Invest. 120, 446–456 (2010).
Wu, X. et al. Regulation of RNA-polymerase-II-dependent transcription by N-WASP and its nuclear-binding partners. Nature Cell Biol. 8, 756–763 (2006).
Zuchero, J. B., Coutts, A. S., Quinlan, M. E., Thangue, N. B. & Mullins, R. D. p53-cofactor JMY is a multifunctional actin nucleation factor. Nature Cell Biol. 11, 451–459 (2009).
Coutts, A. S., Weston, L. & La Thangue, N. B. A transcription co-factor integrates cell adhesion and motility with the p53 response. Proc. Natl Acad. Sci. USA 106, 19872–19877 (2009). References 106 and 107 identify the p53 transcriptional regulator JMY as a potent actin nucleation factor that, when expressed in the cytoplasm, mediates proinvasive cancer cell motility.
Saadi, A. et al. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc. Natl Acad. Sci. USA 107, 2177–2182 (2010).
Bear, J. E. & Gertler, F. B. Ena/VASP: towards resolving a pointed controversy at the barbed end. J. Cell Sci. 122, 1947–1953 (2009).
Pula, G. & Krause, M. Role of Ena/VASP proteins in homeostasis and disease. Handb Exp. Pharmacol. 39–65 (2008).
Bear, J. E. et al. Antagonism between Ena/VASP proteins and actin filament capping regulates fibroblast motility. Cell 109, 509–521 (2002).
Breitsprecher, D. et al. Clustering of VASP actively drives processive, WH2 domain-mediated actin filament elongation. EMBO J. 27, 2943–2954 (2008).
Grosse, R., Copeland, J. W., Newsome, T. P., Way, M. & Treisman, R. A role for VASP in RhoA-Diaphanous signalling to actin dynamics and SRF activity. EMBO J. 22, 3050–3061 (2003).
Dent, E. W. et al. Filopodia are required for cortical neurite initiation. Nature Cell Biol. 9, 1347–1359 (2007).
Scott, J. A. et al. Ena/VASP proteins can regulate distinct modes of actin organization at cadherin-adhesive contacts. Mol. Biol. Cell 17, 1085–1095 (2006).
Bear, J. E. et al. Negative regulation of fibroblast motility by Ena/VASP proteins. Cell 101, 717–728 (2000).
Lambrechts, A. et al. cAMP-dependent protein kinase phosphorylation of EVL, a Mena/VASP relative, regulates its interaction with actin and SH3 domains. J. Biol. Chem. 275, 36143–36151 (2000).
Goswami, S. et al. Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin. Exp. Metastasis 26, 153–159 (2009).
Philippar, U. et al. A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev. Cell 15, 813–828 (2008). This interesting work examines the role of a MENA invasion isoform in driving EGF-dependent breast cancer invasion and metastasis in vivo.
Di Modugno, F. et al. The cytoskeleton regulatory protein hMena (ENAH) is overexpressed in human benign breast lesions with high risk of transformation and human epidermal growth factor receptor-2-positive/hormonal receptor-negative tumors. Clin. Cancer Res. 12, 1470–1478 (2006).
Toyoda, A. et al. Aberrant expression of human ortholog of mammalian enabled (hMena) in human colorectal carcinomas: implications for its role in tumor progression. Int. J. Oncol. 34, 53–60 (2009).
Hu, L. D., Zou, H. F., Zhan, S. X. & Cao, K. M. EVL (Ena/VASP-like) expression is up-regulated in human breast cancer and its relative expression level is correlated with clinical stages. Oncol. Rep. 19, 1015–1020 (2008).
Hasegawa, Y., Murph, M., Yu, S., Tigyi, G. & Mills, G. B. Lysophosphatidic acid (LPA)-induced vasodilator-stimulated phosphoprotein mediates lamellipodia formation to initiate motility in PC-3 prostate cancer cells. Mol. Oncol. 2, 54–69 (2008).
Peterson, J. R. et al. Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation. Nature Struct. Mol. Biol. 11, 747–755 (2004).
Nolen, B. J. et al. Characterization of two classes of small molecule inhibitors of Arp2/3 complex. Nature 460, 1031–1034 (2009).
Gauvin, T. J., Fukui, J., Peterson, J. R. & Higgs, H. N. Isoform-selective chemical inhibition of mDia-mediated actin assembly. Biochemistry 48, 9327–9329 (2009).
Rizvi, S. A. et al. Identification and characterization of a small molecule inhibitor of formin-mediated actin assembly. Chem. Biol. 16, 1158–1168 (2009).
To, C., Shilton, B. H. & Di Guglielmo, G. M. Synthetic triterpenoids target the ARP2/3 complex and inhibit branched actin polymerization. J. Biol. Chem. 285, 27944–27957 (2010).
Chen, L., Yang, S., Jakoncic, J., Zhang, J. J. & Huang, X. Y. Migrastatin analogues target fascin to block tumour metastasis. Nature 464, 1062–1066 (2010).
Shan, D. et al. Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice. Proc. Natl Acad. Sci. USA 102, 3772–3776 (2005).
Fackler, O. T. & Grosse, R. Cell motility through plasma membrane blebbing. The Journal of Cell Biology 181, 879–884 (2008).
Charras, G. & Paluch, E. Blebs lead the way: how to migrate without lamellipodia. Nature Rev. Mol. Cell Biol. 9, 730–736 (2008).
Wu, X., Suetsugu, S., Cooper, L. A., Takenawa, T. & Guan, J. L. Focal adhesion kinase regulation of N-WASP subcellular localization and function. J. Biol. Chem. 279, 9565–9576 (2004).
Brandt, D. T. & Grosse, R. Get to grips: steering local actin dynamics with IQGAPs. EMBO Rep. 8, 1019–1023 (2007).
Martin, T. A., Pereira, G., Watkins, G., Mansel, R. E. & Jiang, W. G. N-WASP is a putative tumour suppressor in breast cancer cells, in vitro and in vivo, and is associated with clinical outcome in patients with breast cancer. Clin. Exp. Metastasis 25, 97–108 (2008).
Yang, L. Y. et al. Increased expression of Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2 correlated with poor prognosis of hepatocellular carcinoma. Clin. Cancer Res. 12, 5673–5679 (2006).
Semba, S. et al. Coexpression of actin-related protein 2 and Wiskott-Aldrich syndrome family verproline-homologous protein 2 in adenocarcinoma of the lung. Clin. Cancer Res. 12, 2449–2454 (2006).
Bringuier, P. P., Tamimi, Y., Schuuring, E. & Schalken, J. Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. Oncogene 12, 1747–1753 (1996).
Hui, R. et al. EMS1 amplification can occur independently of CCND1 or INT-2 amplification at 11q13 and may identify different phenotypes in primary breast cancer. Oncogene 15, 1617–1623 (1997).
Hui, R. et al. EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival. Oncogene 17, 1053–1059 (1998).
Lee, Y. Y. et al. Expression of survivin and cortactin in colorectal adenocarcinoma: association with clinicopathological parameters. Dis. Markers 26, 9–18 (2009).
Cai, J. H. et al. Expression of cortactin correlates with a poor prognosis in patients with stages II-III colorectal adenocarcinoma. J. Gastrointest Surg. 14, 1248–1257 (2010).
Wang, X. et al. VEGF and cortactin expression are independent predictors of tumor recurrence following curative resection of gastric cancer. J. Surg. Oncol. 102, 325–330 (2010).
Xie, H. L. et al. Differential gene and protein expression in primary gastric carcinomas and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis. J. Dig Dis. 11, 167–175 (2010).
Tsai, W. C. et al. Association of cortactin and fascin-1 expression in adenocarcinoma: correlation with clinicopathological parameters. J. Histochem. Cytochem. 55, 955–962 (2007).
Li, X. et al. Aberrant expression of cortactin and fascin are effective markers for pathogenesis, invasion, metastasis and prognosis of gastric carcinomas. Int. J. Oncol. 33, 69–79 (2008).
Gibcus, J. H. et al. Cortactin expression predicts poor survival in laryngeal carcinoma. Br. J. Cancer 98, 950–955 (2008).
Rodrigo, J. P. et al. Distinctive clinicopathological associations of amplification of the cortactin gene at 11q13 in head and neck squamous cell carcinomas. J. Pathol. 217, 516–523 (2009).
Hsu, K. F. et al. Cortactin, fascin, and survivin expression associated with clinicopathological parameters in esophageal squamous cell carcinoma. Dis. Esophagus 22, 402–408 (2009).
Takes, R. P. et al. Markers for assessment of nodal metastasis in laryngeal carcinoma. Arch. Otolaryngol. Head Neck Surg. 123, 412–419 (1997).
Xu, X. Z. et al. Cytoskeleton alterations in melanoma: aberrant expression of cortactin, an actin-binding adapter protein, correlates with melanocytic tumor progression. Mod. Pathol. 23, 187–196 (2010).
Yamada, S. I., Yanamoto, S., Kawasaki, G., Mizuno, A. & Nemoto, T. K. Overexpression of cortactin increases invasion potential in oral squamous cell carcinoma. Pathol. Oncol. Res. 16, 523–531 (2010).
Lin, C. K., Su, H. Y., Tsai, W. C., Sheu, L. F. & Jin, J. S. Association of cortactin, fascin-1 and epidermal growth factor receptor (EGFR) expression in ovarian carcinomas: correlation with clinicopathological parameters. Dis. Markers 25, 17–26 (2008).
Wang, G. C. et al. Expression of cortactin and survivin in renal cell carcinoma associated with tumor aggressiveness. World J. Urol. 27, 557–563 (2009).
Dertsiz, L. et al. Differential expression of VASP in normal lung tissue and lung adenocarcinomas. Thorax 60, 576–581 (2005).
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.
The authors declare no competing financial interests.
- 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.
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.
A middle layer of the eye surface located between sclera and retina.
About this article
Cite this article
Nürnberg, A., Kitzing, T. & Grosse, R. Nucleating actin for invasion. Nat Rev Cancer 11, 177–187 (2011). https://doi.org/10.1038/nrc3003
This article is cited by
Cav2.2-NFAT2-USP43 axis promotes invadopodia formation and breast cancer metastasis through cortactin stabilization
Cell Death & Disease (2022)
Nature Communications (2022)
Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies
Nature Communications (2021)
Cellular Oncology (2021)
Cellular and Molecular Neurobiology (2021)