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.
Highlights
To cite this version: Clément Chevalier, Guillaume Collin, Simon Descamps, Heiani Touaitahuata, Valérie Simon, et al
We demonstrate that TOM1L1 enhances ERBB2-induced cell invasiveness by promoting invadopodia formation and membrane-type 1 matrix metalloproteases (MMPs) (MT1-MMP) trafficking to the plasma membrane
Metastasis-free survival was reduced in patients with ERBB2 þ /ER þ breast cancer in which TOM1L1 was amplified compared with those without TOM1L1 amplification (Fig. 1e)
Summary
To cite this version: Clément Chevalier, Guillaume Collin, Simon Descamps, Heiani Touaitahuata, Valérie Simon, et al. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. 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. 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. 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. There is an urgent need to better understand the molecular basis of ERBB2-induced metastatic malignancy for developing new targeted treatments
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