Secreted and membrane-bound isoforms of protease ADAM9 have opposing effects on breast cancer cell migration.
Secreted and membrane-bound isoforms of protease ADAM9 have opposing effects on breast cancer cell migration.
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DOI：
10.1158/0008-5472.can-09-4231
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Toker A
中科院分区：
文献类型：
--
作者：
Fry JL;Toker A
肿瘤细胞迁移是由细胞自主信号机制以及肿瘤微环境中激活的基质细胞分泌的旁分泌和自分泌因子介导的。与ADAM家族的其他成员一样，整合素结合金属蛋白酶ADAM 9调节细胞-细胞和细胞-基质相互作用以及细胞表面受体和配体的胞外域脱落，从而修饰细胞内和细胞外信号传导。ADAM 9转录物选择性剪接以表达跨膜蛋白（ADAM 9-L）和分泌变体（ADAM 9-S）。在这项研究中，我们表明，ADAM 9-S促进乳腺癌细胞迁移的方式需要其金属蛋白酶活性，而ADAM 9-L抑制细胞迁移独立于其金属蛋白酶活性。ADAM 9-L对迁移的抑制需要功能性去整合素结构域和整合素结合。表达分析显示，两种ADAM 9亚型在乳腺癌细胞系和组织中表达。因此，ADAM 9的膜束缚和分泌变体的相对水平是与乳腺癌进展相关的侵袭性迁移表型表现的关键决定因素。
Tumor cell migration is mediated by cell autonomous signaling mechanisms as well as paracrine and autocrine factors secreted by activated stromal cells in the tumor microenvironment. Like other members of the ADAM family, the integrin-binding metalloprotease ADAM9 modulates cell-cell and cell-matrix interactions as well as ectodomain shedding of cell surface receptors and ligands, thereby modifying intracellular and extracellular signaling. ADAM9 transcripts are alternatively spliced to express a transmembrane protein (ADAM9-L) and a secreted variant (ADAM9-S). In this study, we show that ADAM9-S promotes breast cancer cell migration in a manner requiring its metalloprotease activity, whereas ADAM9-L suppresses cell migration independent of its metalloprotease activity. Suppression of migration by ADAM9-L requires a functional disintegrin domain and integrin binding. Expression analysis revealed that both ADAM9 isoforms are expressed in breast cancer cell lines and tissues. Therefore, relative levels of membrane-tethered and secreted variants of ADAM9 are a key determinant in manifestation of aggressive migratory phenotypes associated with breast cancer progression.