TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion.
TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion.
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DOI：
10.1038/ncomms10765
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发表时间：
2016-02-22
影响因子：
16.6
通讯作者：
Benistant C
中科院分区：
文献类型：
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作者：
Chevalier C;Collin G;Descamps S;Touaitahuata H;Simon V;Reymond N;Fernandez L;Milhiet PE;Georget V;Urbach S;Lasorsa L;Orsetti B;Boissière-Michot F;Lopez-Crapez E;Theillet C;Roche S;Benistant C
ERBB2在人乳腺癌中的过表达可导致浸润性癌，但其机制尚不清楚。在这里，我们报告TOM1L1与ERBB2共同扩增，并定义了早期转移性复发的HER2+/ER+肿瘤亚组。TOM1L1编码含有GAT结构域的转运蛋白，是负调控酪氨酸激酶信号传导的SRC底物。我们证明TOM1L1上调可增强erbb2转化细胞的侵袭性。这种促肿瘤功能不涉及SRC，但涉及膜结合膜型1 MMP （MT1-MMP）依赖的浸润性激活，细胞外基质降解的膜突起。从机制上讲，ERBB2诱导TOM1L1在Ser321上的间接磷酸化。磷酸化事件促进了gat依赖的TOM1L1与分选蛋白TOLLIP的关联，以及金属蛋白酶MT1-MMP从内吞室转运到肿瘤细胞侵袭的内殖体。总的来说，这些结果表明TOM1L1是erbb2驱动的蛋白溶解侵袭程序的重要组成部分，并且TOM1L1扩增可能会促进erbb2阳性乳腺癌的转移进展。ERBB2在人乳腺癌中的过度表达导致乳腺癌的侵袭和转移。本文作者报道，ERBB2诱导TOM1L1的间接磷酸化，促进金属蛋白酶MT1-MMP的运输，从而导致肿瘤细胞侵袭。
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. ERBB2 overexpression in human breast cancer leads to invasion and metastasis. Here the authors report that ERBB2 induces indirect phosphorylation of TOM1L1 that promotes trafficking of the metalloprotease MT1-MMP to invadopodia, which leads to tumour cell invasion.