title: TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion.
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.
authors.affiliation: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293 Montpellier, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Chevalier
authors.affiliation: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293 Montpellier, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Collin
authors.affiliation: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293 Montpellier, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Descamps
authors.affiliation: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293 Montpellier, France.
authors.forename: Heiani
authors.initials: H
authors.lastname: Touaitahuata
authors.affiliation: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293 Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Simon
authors.affiliation: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293 Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Reymond
authors.affiliation: Centre de Biochimie Structurale, CNRS UMR 5048-INSERM UMR 1054, 29 rue de navacelles, 34090 Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Fernandez
authors.affiliation: Centre de Biochimie Structurale, CNRS UMR 5048-INSERM UMR 1054, 29 rue de navacelles, 34090 Montpellier, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Milhiet
authors.affiliation: Montpellier RIO Imaging Facility, 34293 Montpellier, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Georget
authors.affiliation: Functional Proteomics Platform, 34090 Montpellier, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Urbach
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM U896, 34298 Montpellier, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lasorsa
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM U896, 34298 Montpellier, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Orsetti
authors.affiliation: Translational Research Unit, Institut régional du Cancer de Montpellier (ICM)-Val d'Aurelle, 34298 Montpellier, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Boissière-Michot
authors.affiliation: Translational Research Unit, Institut régional du Cancer de Montpellier (ICM)-Val d'Aurelle, 34298 Montpellier, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lopez-Crapez
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier; INSERM U896, 34298 Montpellier, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Theillet
authors.affiliation: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293 Montpellier, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Roche
authors.affiliation: Montpellier University, Centre de Recherche de Biochimie Macromoléculaire, CNRS UMR 5237, 34293 Montpellier, France.|Centre de Biochimie Structurale, CNRS UMR 5048-INSERM UMR 1054, 29 rue de navacelles, 34090 Montpellier, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Benistant
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D053511:Matrix Metalloproteinase 14; D018719:Erb-b2 Receptor Tyrosine Kinases; C410602:TOLLIP protein, human; C499446:TOM1L1 protein, human