Maretzky Thorsten, Le Gall Sylvain M, Worpenberg-Pietruk Susanne, Eder Jörg, Overall Christopher M, Huang Xin-Yun, Poghosyan Zaruhi, Edwards Dylan R, Blobel Carl P
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, and Department of Physiology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Cancer Res. 2009 Jun 1;69(11):4573-6. doi: 10.1158/0008-5472.CAN-08-4766.
ADAMs (a disintegrin and metalloproteinase) have important roles in development and diseases such as cancer. Previously, an ADAM15 splice variant (ADAM15B), which contains an inserted cytoplasmic Src-binding site, was linked to clinical aggressiveness in breast cancer, yet little was known about how this splice variant affects the function of ADAM15. Here, we show that ADAM15B has enhanced catalytic activity in cell-based assays compared with ADAM15A, which lacks a Src-binding site, using shedding of fibroblast growth factor receptor 2iiib variant as an assay for catalytic activity. Moreover, the enhanced activity of ADAM15B compared with ADAM15A depends on Src because it is abolished by Src-kinase inhibitors and in Src(-/-) cells, but not in Src(-/-) cells rescued with Src. These findings provide insights into the mechanism of how a splice variant linked to clinical agressiveness in breast cancer causes increased activity of ADAM15B, and suggest that inhibitors of the ADAM15 protease activity or of the interaction of ADAM15B with Src could be useful to treat breast cancer in patients with dysregulated ADAM15B.
解整合素金属蛋白酶（ADAMs）在发育以及癌症等疾病中发挥着重要作用。此前，一种包含插入的细胞质Src结合位点的ADAM15剪接变体（ADAM15B）与乳腺癌的临床侵袭性有关，但对于这种剪接变体如何影响ADAM15的功能却知之甚少。在此，我们发现，与缺乏Src结合位点的ADAM15A相比，在基于细胞的检测中，ADAM15B具有更高的催化活性，检测方法是利用成纤维细胞生长因子受体2iiib变体的脱落来检测催化活性。此外，与ADAM15A相比，ADAM15B活性的增强依赖于Src，因为Src激酶抑制剂以及在Src基因敲除细胞中这种增强活性会消失，但在用Src挽救的Src基因敲除细胞中则不会消失。这些发现为与乳腺癌临床侵袭性相关的剪接变体如何导致ADAM15B活性增加的机制提供了见解，并表明ADAM15蛋白酶活性抑制剂或ADAM15B与Src相互作用的抑制剂可能有助于治疗ADAM15B失调的乳腺癌患者。
