Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:35795.

Proteomic screening identifies the zonula occludens protein ZO-1 as a new partner for ADAM12 in invadopodia-like structures

Bassil Dekky, Michael Ruff, Dominique Bonnier, Vincent Legagneux and Nathalie Théret _

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Oncotarget. 2018; 9:21366-21382. https://doi.org/10.18632/oncotarget.25106

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Bassil Dekky1, Michael Ruff1,2,*, Dominique Bonnier1,*, Vincent Legagneux1 and Nathalie Théret1

1Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S1085, Rennes, France

2Present address: Institute of Biology Valrose (iBV) CNRS UMR7277 - INSERM U1091 – UNS University Nice Sophia Antipolis, Nice, France

*These authors contributed equally to this work

Correspondence to:

Nathalie Théret, email: [email protected]

Vincent Legagneux, email: [email protected]

Keywords: ADAM12; ZO-1; invadopodia; EMT; cancer

Abbreviations: ADAM: a disintegrin and metalloprotease; EMT: epithelial mesenchymal transition; ECM: extracellular matrix; TGF-β: transforming growth factor-beta; siRNA: small interfering RNA

Received: September 06, 2017     Accepted: March 23, 2018     Published: April 20, 2018


The epithelial mesenchymal transition (EMT) is a key process for cancer cell invasion and migration. This complex program whereby epithelial tumor cells loose polarity and acquire mesenchymal phenotype is driven by the regulation of cell-cell adhesion and cell-substrate interactions. We recently described the association of ADAM12 with EMT and we now use immunoprecipitation and proteomic approaches to identify interacting partners for ADAM12 during EMT. We identify twenty proteins that are involved in molecular mechanisms associated with adhesion/invasion processes. Integrative network analyses point out the zonula occludens protein ZO-1, as a new potential partner for ADAM12. In silico screening demonstrates that ZO-1 and ADAM12 are coexpressed in breast cancer cell lines sharing EMT signature. We validate the interaction between ZO-1 and ADAM12 in invasive breast cancer cell lines and show that ZO-1 and ADAM12 co-localize in actin- and cortactin-rich structures. Silencing either ADAM12 or ZO-1 inhibits gelatin degradation demonstrating that both proteins are required for matrix degradation. We further show that matrix metalloprotease 14, known to mediate degradation of collagen in invadopodia-like structures interacts with ZO-1. Depletion of PKCε that regulates the recruitment of ADAM12 and ZO-1 to cell membranes induces a decrease in ADAM12 and ZO-1 at invadopodia-like structures and degradation activity. Together our data provide evidence for a new interaction between ADAM12, a mesenchymal marker induced during TGF-β-dependent EMT and ZO-1, a scaffolding protein expressed in tight junctions of epithelial cells, both proteins being redistributed at the invadopodia-like structures of mesenchymal invasive cells to promote PKCε-dependent matrix degradation.

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