The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation
The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation
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DOI：
10.1074/jbc.m801329200
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发表时间：
2008-06-27
影响因子：
4.8
通讯作者：
Day, Mark L.
中科院分区：
文献类型：
--
作者：
Najy, Abdo J.;Day, Kathleen C.;Day, Mark L.
锌依赖性去整合素金属蛋白酶（adintegrin and metalloproteinases，亚当斯）参与了多种疾病，包括人类癌症。以前，我们证明了ADAM家族的催化活性成员ADAM 15的表达与前列腺癌和乳腺癌的进展有关。人血清中E-钙粘蛋白的可溶性胞外域的积累也与前列腺癌和乳腺癌的进展相关，并且被认为是由金属蛋白酶脱落介导的。利用两个互补的模型，过表达和稳定的短发夹RNA介导的乳腺癌细胞中的ADAM 15敲低，我们证明了ADAM 15切割E-钙粘蛋白在响应生长因子剥夺。我们还证明了E-钙粘蛋白的细胞外脱落被金属蛋白酶抑制剂和通过在ADAM 15中引入催化失活突变而废除。我们已经做出了新的观察，发现这种可溶性E-钙粘蛋白片段与乳腺癌细胞中的HER 2和HER 3受体复合。这些相互作用似乎稳定了HER 2与HER 3的异源二聚化，并通过Erk途径诱导受体活化和信号传导，支持细胞迁移和增殖。在这项研究中，我们提供的证据表明，ADAM 15催化切割E-钙粘蛋白，产生一个可溶性片段，反过来结合并刺激ErbB受体信号。
The zinc-dependent disintegrin metalloproteinases (a disintegrin and metalloproteinases (ADAMs) have been implicated in several disease processes, including human cancer. Previously, we demonstrated that the expression of a catalytically active member of the ADAM family, ADAM15, is associated with the progression of prostate and breast cancer. The accumulation of the soluble ectodomain of E-cadherin in human serum has also been associated with the progression of prostate and breast cancer and is thought to be mediated by metalloproteinase shedding. Utilizing two complementary models, overexpression and stable short hairpin RNA-mediated knockdown of ADAM15 in breast cancer cells, we demonstrated that ADAM15 cleaves E-cadherin in response to growth factor deprivation. We also demonstrated that the extracellular shedding of E-cadherin was abrogated by a metalloproteinase inhibitor and through the introduction of a catalytically inactive mutation in ADAM15. We have made the novel observation that this soluble E-cadherin fragment was found in complex with the HER2 and HER3 receptors in breast cancer cells. These interactions appeared to stabilize HER2 heterodimerization with HER3 and induced receptor activation and signaling through the Erk pathway, supporting both cell migration and proliferation. In this study, we provide evidence that ADAM15 catalyzes the cleavage of E-cadherin to generate a soluble fragment that in turn binds to and stimulates ErbB receptor signaling.