Huang Jing, Bridges Lance C, White Judith M
Department of Cell Biology, School of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA.
Mol Biol Cell. 2005 Oct;16(10):4982-91. doi: 10.1091/mbc.e05-03-0258. Epub 2005 Aug 3.
A disintegrin and a metalloprotease (ADAM) family members have been implicated in many biological processes. Although it is recognized that recombinant ADAM disintegrin domains can interact with integrins, little is known about ADAM-integrin interactions in cellular context. Here, we tested whether ADAMs can selectively regulate integrin-mediated cell migration. ADAMs were expressed in Chinese hamster ovary cells that express defined integrins (alpha4beta1, alpha5beta1, or both), and cell migration on full-length fibronectin or on its alpha4beta1 or alpha5beta1 binding fragments was studied. We found that ADAMs inhibit integrin-mediated cell migration in patterns dictated by the integrin binding profiles of their isolated disintegrin domains. ADAM12 inhibited cell migration mediated by the alpha4beta1 but not the alpha5beta1 integrin. ADAM17 had the reciprocal effect; it inhibited alpha5beta1- but not alpha4beta1-mediated cell migration. ADAM19 and ADAM33 inhibited migration mediated by both alpha4beta1 and alpha5beta1 integrins. A point mutation in the ADAM12 disintegrin loop partially reduced the inhibitory effect of ADAM12 on cell migration on the alpha4beta1 binding fragment of fibronectin, whereas mutations that block metalloprotease activity had no effect. Our results indicate that distinct ADAMs can modulate cell migration mediated by specific integrins in a pattern dictated, at least in part, by their disintegrin domains.
解聚素和金属蛋白酶（ADAM）家族成员参与了许多生物学过程。尽管人们认识到重组ADAM解聚素结构域可与整合素相互作用，但对于细胞环境中ADAM与整合素的相互作用却知之甚少。在此，我们测试了ADAM是否能选择性地调节整合素介导的细胞迁移。将ADAM在中国仓鼠卵巢细胞中表达，这些细胞表达特定的整合素（α4β1、α5β1或两者皆有），并研究细胞在全长纤连蛋白或其α4β1或α5β1结合片段上的迁移情况。我们发现，ADAM以其分离的解聚素结构域的整合素结合谱所决定的模式抑制整合素介导的细胞迁移。ADAM12抑制由α4β1整合素介导的细胞迁移，但不抑制α5β1整合素介导的细胞迁移。ADAM17则有相反的作用；它抑制由α5β1整合素介导的细胞迁移，但不抑制α4β1整合素介导的细胞迁移。ADAM19和ADAM33抑制由α4β1和α5β1整合素介导的迁移。ADAM12解聚素环中的一个点突变部分降低了ADAM12对细胞在纤连蛋白α4β1结合片段上迁移的抑制作用，而阻断金属蛋白酶活性的突变则没有影响。我们的结果表明，不同的ADAM可以以至少部分由其解聚素结构域决定的模式调节特定整合素介导的细胞迁移。
