TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion

Clément Chevalier, Guillaume Collin, Simon Descamps, Heiani Touaitahuata, Valérie Simon, Nicolas Reymond, Laurent Fernandez, Pierre-Emmanuel Milhiet, Virginie Georget, Serge Urbach, Laurence Lasorsa, Béatrice Orsetti, Florence Boissière-Michot, Evelyne Lopez-Crapez, Charles Theillet, Serge Roche () and Christine Benistant ()
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Clément Chevalier: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
Guillaume Collin: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
Simon Descamps: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
Heiani Touaitahuata: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
Valérie Simon: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
Nicolas Reymond: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
Laurent Fernandez: Centre de Biochimie Structurale, CNRS UMR 5048-INSERM UMR 1054, 29 rue de navacelles, 34090 Montpellier, France
Pierre-Emmanuel Milhiet: Centre de Biochimie Structurale, CNRS UMR 5048-INSERM UMR 1054, 29 rue de navacelles, 34090 Montpellier, France
Virginie Georget: Montpellier RIO Imaging Facility
Serge Urbach: Functional Proteomics Platform
Laurence Lasorsa: IRCM, Institut de Recherche en Cancérologie de Montpellier
Béatrice Orsetti: IRCM, Institut de Recherche en Cancérologie de Montpellier
Florence Boissière-Michot: Translational Research Unit, Institut régional du Cancer de Montpellier (ICM)-Val d'Aurelle
Evelyne Lopez-Crapez: Translational Research Unit, Institut régional du Cancer de Montpellier (ICM)-Val d'Aurelle
Charles Theillet: IRCM, Institut de Recherche en Cancérologie de Montpellier
Serge Roche: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
Christine Benistant: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract ERBB2 overexpression in human breast cancer leads to invasive carcinoma but the mechanism is not clearly understood. Here we report that TOM1L1 is co-amplified with ERBB2 and defines a subgroup of HER2+/ER+ tumours with early metastatic relapse. TOM1L1 encodes a GAT domain-containing trafficking protein and is a SRC substrate that negatively regulates tyrosine kinase signalling. We demonstrate that TOM1L1 upregulation enhances the invasiveness of ERBB2-transformed cells. This pro-tumoural function does not involve SRC, but implicates membrane-bound membrane-type 1 MMP (MT1-MMP)-dependent activation of invadopodia, membrane protrusions specialized in extracellular matrix degradation. Mechanistically, ERBB2 elicits the indirect phosphorylation of TOM1L1 on Ser321. The phosphorylation event promotes GAT-dependent association of TOM1L1 with the sorting protein TOLLIP and trafficking of the metalloprotease MT1-MMP from endocytic compartments to invadopodia for tumour cell invasion. Collectively, these results show that TOM1L1 is an important element of an ERBB2-driven proteolytic invasive programme and that TOM1L1 amplification potentially enhances the metastatic progression of ERBB2-positive breast cancers.

Date: 2016
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DOI: 10.1038/ncomms10765

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