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

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  • Clément Chevalier

    (Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
    Present addresses: SFR Biosit, CNRS UMS 3480/INSERM US 018, MRic photonics platform, University Rennes 1, 35043 Rennes, France)

  • Guillaume Collin

    (Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
    Present addresses: Centre de Recherche en Cancérologie de Lyon, Inserm UMR-S1052, 69373 Lyon, France)

  • 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
    INSERM U896)

  • Béatrice Orsetti

    (IRCM, Institut de Recherche en Cancérologie de Montpellier
    INSERM U896)

  • 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
    INSERM U896)

  • Serge Roche

    (Montpellier University, Centre de Recherche de Biochimie Macromoléculaire)

  • Christine Benistant

    (Montpellier University, Centre de Recherche de Biochimie Macromoléculaire
    Centre de Biochimie Structurale, CNRS UMR 5048-INSERM UMR 1054, 29 rue de navacelles, 34090 Montpellier, France)

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.

Suggested Citation

  • Clément Chevalier & Guillaume Collin & Simon Descamps & Heiani Touaitahuata & Valérie Simon & Nicolas Reymond & Laurent Fernandez & Pierre-Emmanuel Milhiet & Virginie Georget & Serge Urbach & Laurence, 2016. "TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion," Nature Communications, Nature, vol. 7(1), pages 1-16, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10765
    DOI: 10.1038/ncomms10765
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