Zhang Zhi-Gang, Bothe Ingo, Hirche Frank, Zweers Manon, Gullberg Donald, Pfitzer Gabriele, Krieg Thomas, Eckes Beate, Aumailley Monique
Department of Dermatology, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
J Cell Sci. 2006 May 1;119(Pt 9):1886-95. doi: 10.1242/jcs.02921.
The alpha2beta1 integrin is a collagen-binding protein with very high affinity for collagen I. It also binds several other collagens and laminins and it is expressed by many cells, including keratinocytes and fibroblasts in the skin. In the past, alpha2beta1 integrin was suggested to be responsible for cell attachment, spreading and migration on monomeric collagen I and contraction of three-dimensional collagen lattices. In view of these functions, normal development and fertility in integrin alpha2-deficient mice, which we generated by targeting the integrin alpha2 gene, came as a surprise. This suggested the existence of compensatory mechanisms that we investigate here using primary fibroblasts and keratinocytes isolated from wild-type and alpha2-deficient mice, antibodies blocking integrin function and downregulation of integrin alpha2 expression. The results show that the alpha2beta1 integrin is absolutely required for keratinocyte adhesion to collagens whereas for fibroblasts other collagen-binding integrins partially back-up the lack of alpha2beta1 in simple adhesion to collagen monomers. A prominent requirement for alpha2beta1 integrins became apparent when fibroblasts executed mechanical tasks of high complexity in three-dimensional surroundings, such as contracting free-floating collagen gels and developing isometric forces in tethered lattices. The deficits observed for alpha2-deficient fibroblasts appeared to be linked to alterations in the distribution of force-bearing focal adhesions and deregulation of Rho-GTPase activation.
α2β1整合素是一种对I型胶原具有极高亲和力的胶原结合蛋白。它还能结合其他几种胶原和层粘连蛋白，并且在包括皮肤中的角质形成细胞和成纤维细胞在内的许多细胞中表达。过去，α2β1整合素被认为负责细胞在单体I型胶原上的附着、铺展和迁移以及三维胶原晶格的收缩。鉴于这些功能，我们通过靶向整合素α2基因产生的整合素α2缺陷小鼠的正常发育和生育能力令人惊讶。这表明存在补偿机制，我们在此使用从野生型和α2缺陷小鼠分离的原代成纤维细胞和角质形成细胞、阻断整合素功能的抗体以及整合素α2表达的下调来研究这些机制。结果表明，角质形成细胞黏附于胶原绝对需要α2β1整合素，而对于成纤维细胞，其他胶原结合整合素在简单黏附于胶原单体时部分弥补了α2β1的缺失。当成纤维细胞在三维环境中执行高复杂性的机械任务时，例如收缩自由漂浮的胶原凝胶并在系留晶格中产生等长力时，对α2β1整合素的显著需求变得明显。α2缺陷成纤维细胞中观察到的缺陷似乎与承载应力的黏着斑分布改变和Rho-GTPase激活失调有关。
