Chevalier Clément, Collin Guillaume, Descamps Simon, Touaitahuata Heiani, Simon Valérie, Reymond Nicolas, Fernandez Laurent, Milhiet Pierre-Emmanuel, Georget Virginie, Urbach Serge, Lasorsa Laurence, Orsetti Béatrice, Boissière-Michot Florence, Lopez-Crapez Evelyne, Theillet Charles, Roche Serge, Benistant Christine
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.
Nat Commun. 2016 Feb 22;7:10765. doi: 10.1038/ncomms10765.
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.
人乳腺癌中ERBB2的过表达会导致浸润性癌，但其机制尚不清楚。在此我们报告，TOM1L1与ERBB2共同扩增，并定义了一组HER2(+)/ER(+)肿瘤亚群，这些肿瘤具有早期转移复发的特点。TOM1L1编码一种含GAT结构域的转运蛋白，是一种SRC底物，可负向调节酪氨酸激酶信号传导。我们证明，TOM1L1的上调增强了ERBB2转化细胞的侵袭性。这种促肿瘤功能不涉及SRC，但与膜结合的膜型1基质金属蛋白酶（MT1-MMP）依赖性的侵袭伪足激活有关，侵袭伪足是专门负责细胞外基质降解的膜突出结构。从机制上来说，ERBB2可引发TOM1L1第321位丝氨酸的间接磷酸化。该磷酸化事件促进了TOM1L1与分选蛋白TOLLIP的GAT依赖性结合，以及金属蛋白酶MT1-MMP从内吞区室向侵袭伪足的转运，以促进肿瘤细胞侵袭。总的来说，这些结果表明，TOM1L1是ERBB2驱动的蛋白水解侵袭程序的重要组成部分，并且TOM1L1的扩增可能会增强ERBB2阳性乳腺癌的转移进程。
