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Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation

A Corrigendum to this article was published on 14 April 2011

Abstract

Migration of cells and degradation of the extracellular matrix (ECM) are required for efficient tumor cell invasion, but the underlying molecular mechanisms are only partially known. The PPFIA1 gene for liprin-α1 is frequently amplified in human breast cancers. We recently demonstrated that liprin-α1 is an important regulator of cell edge dynamics during motility. We show, herein, that the liprin-α1 protein is highly expressed in human breast tumors. Functional analysis shows that liprin-α1 is specifically required for the migration and invasion of highly invasive human breast cancer MDA-MB-231 cells. We used time-lapse analysis to demonstrate defects in the motility of liprin-α1-depleted cells that include a striking instability of the lamellipodia. Liprin-α1 levels altered by either RNA interference or overexpression affected also cell spreading and the number of invadopodia per cell, but not the density of invadopodia per unit of surface area. On the other hand, silencing of liprin-α1 inhibited the degradation of the ECM, whereas its overexpression enhanced degradation, resulting in significant negative or positive effects, respectively, on the area of degradation per invadopodium. Transfection of fluorescent-labeled cortactin revealed that depletion of liprin-α1 also affected the assembly and disassembly of invadopodia, with decrease of their lifetime. Our results strongly support a novel important role of liprin-α1 in the regulation of human tumor cell invasion.

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References

  • Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H et al. (2004). Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 64: 8534–8540.

    Article  CAS  PubMed  Google Scholar 

  • Albiges-Rizo C, Destaing O, Fourcade B, Planus E, Block MR . (2009). Actin machinery and mechanosensitivity in invadopodia, podosomes and focal adhesions. J Cell Sci 122: 3037–3049.

    Article  CAS  PubMed  Google Scholar 

  • Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM, Mueller SC . (2006). 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.

    Article  CAS  PubMed  Google Scholar 

  • Asperti C, Astro V, Totaro A, Paris S, de Curtis I . (2009). Liprin-alpha1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins. J Cell Sci 122: 3225–3232.

    Article  CAS  PubMed  Google Scholar 

  • Asperti C, Pettinato E, de Curtis I . (2010). Liprin-alpha1 affects the distribution of low-affinity beta1 integrins and stabilizes their permanence at the cell surface. Exp Cell Res 316: 915–926.

    Article  CAS  PubMed  Google Scholar 

  • Cao H, Orth JD, Chen J, Weller SG, Heuser JE, McNiven MA . (2003). Cortactin is a component of clathrin-coated pits and participates in receptor-mediated endocytosis. Mol Cell Biol 23: 2162–2170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Curtis I . (2011). Function of liprins in cell motility. Exp Cell Res 317: 1–8.

    Article  CAS  PubMed  Google Scholar 

  • Frank SR, Adelstein MR, Hansen SH . (2006). GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover. EMBO J 25: 1848–1859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Järvinen AK, Autio R, Haapa-Paananen S, Wolf M, Saarela M, Grénman R et al. (2006). Identification of target genes in laryngeal squamous cell carcinoma by high-resolution copy number and gene expression microarray analyses. Oncogene 25: 6997–7008.

    Article  PubMed  Google Scholar 

  • Katoh M, Katoh M . (2005). Comparative genomics on mammalian Fgf3-Fgf4 locus. Int J Oncol 27: 281–285.

    CAS  PubMed  Google Scholar 

  • Kim S, Chin K, Gray JW, Bishop JM . (2004). A screen for genes that suppress loss of contact inhibition: identification of ING4 as a candidate tumor suppressor gene in human cancer. Proc Natl Acad Sci USA 101: 16251–16256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lenter M, Uhlig H, Hamann A, Jenö P, Imhof B, Vestweber DA . (1993). A monoclonal antibody against an activation epitope on mouse integrin chain beta 1 blocks adhesion of lymphocytes to the endothelial integrin alpha 6 beta 1. Proc Natl Acad Sci USA 90: 9051–9055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nachat R, Cipolat S, Sevilla LM, Chhatriwala M, Groot KR, Watt FM . (2009). KazrinE is a desmosome-associated liprin that colocalises with acetylated microtubules. J Cell Sci 122: 4035–4041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pankov R, Endo Y, Even-Ram S, Araki M, Clark K, Cukierman E et al. (2005). A Rac switch regulates random versus directionally persistent cell migration. J Cell Biol 170: 793–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiao F, Bowie JU . (2005). The many faces of SAM. Sci STKE 2005: re7.

    Article  Google Scholar 

  • Serra-Pagès C, Kedersha NL, Fazikas L, Medley Q, Debant A, Streuli M . (1995). The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions. EMBO J 14: 2827–2838.

    Article  PubMed  PubMed Central  Google Scholar 

  • Serra-Pagès C, Medley QG, Tang M, Hart A, Streuli M . (1998). Liprins, a family of LAR transmembrane protein-tyrosine phosphatase-interacting proteins. J Biol Chem 273: 15611–15620.

    Article  PubMed  Google Scholar 

  • Shaw LM . (2005). Tumor cell invasion assays. Methods Mol Biol 294: 97–105.

    PubMed  Google Scholar 

  • Shen JC, Unoki M, Ythier D, Duperray A, Varticovski L, Kumamoto K et al. (2007). Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. Cancer Res 67: 2552–2558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spangler SA, Hoogenraad CC . (2007). Liprin-alpha proteins: scaffold molecules for synapse maturation. Biochem Soc Trans 35: 1278–1282.

    Article  CAS  PubMed  Google Scholar 

  • Tan KD, Zhu Y, Tan HK, Rajasegaran V, Aggarwal A, Wu J et al. (2008). Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressor gene, in head and neck squamous cell carcinoma. Genes Chromosomes Cancer 47: 353–362.

    Article  CAS  PubMed  Google Scholar 

  • Totaro A, Paris S, Asperti C, de Curtis I . (2007). Identification of an intramolecular interaction important for the regulation of GIT1 functions. Mol Biol Cell 18: 5124–5138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weaver AM . (2008). Invadopodia. Curr Biol 18: R362–R364.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Support to I de Curtis by the AIRC (Italian Association for Cancer Research, grant no. 5060) and by the Italian Telethon Foundation (grant no. GGP09078) is gratefully acknowledged. The plasmid for DsRed-Cortactin was generously provided by Mark A McNiven (Mayo Clinic, Rochester, MN, USA). We thank Cesare Covino of the Alembic facility at our Institute for his support in the morphological analysis, Rosanna Latino and Maurizio Ferrari for the cytogenetic analysis, and Jacopo Meldolesi for critical reading of the manuscript.

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Correspondence to I de Curtis.

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Astro, V., Asperti, C., Cangi, G. et al. Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation. Oncogene 30, 1841–1849 (2011). https://doi.org/10.1038/onc.2010.562

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  • DOI: https://doi.org/10.1038/onc.2010.562

Keywords

  • cell migration
  • invadopodia
  • invasion
  • lamellipodia
  • liprins

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