Cell Biology, Woolcock Institute of Medical Research, PO Box M77, Missenden Rd., NSW, 2050, Australia.
Am J Physiol Lung Cell Mol Physiol. 2012 Oct 15;303(8):L703-10. doi: 10.1152/ajplung.00414.2011. Epub 2012 Aug 24.
Recent evidence suggests that the rare and progressive lung disease lymphangioleiomyomatosis (LAM) is metastatic in nature. Dysfunction of the tumor suppressor genes tuberous sclerosis complex (TSC), in particular mutational inactivation of TSC2, enhances both cell proliferation and migration. Although substantial progress has been made in understanding the role of TSC2 in abnormal LAM cell proliferation and its pharmacological targeting, the mechanisms underlying the enhanced migratory capacity in LAM are not well understood. In this study, we examined the role of TSC2 in cell attachment, spreading, and migration, processes that contribute to the metastatic phenotype. Here we show that loss of TSC2 increased both the attachment and spreading of mouse embryonic fibroblasts to the extracellular matrix proteins collagen type I and fibronectin and that reexpression of TSC2 reduced these effects. Integrin-α1β1 modulated cell migration with the β1-subunit involved in cell attachment and spreading as shown by using functional blocking antibodies. Loss of TSC2 increased integrin-α1 expression, and inhibition of this integrin subunit reduced cell migration. The enhanced attachment and spreading were independent of the intracellular signaling pathways mammalian target of rapamycin complex 1 and Rho-associated kinase, as pharmacological inhibition with rapamycin or Y27632, respectively, was without effect. Together, these data demonstrate that TSC2 controls cell migration, attachment, and spreading through the α1β1-integrin receptor and thus suggest a potential therapeutic target for the treatment of increased cell invasiveness in LAM.
最近的证据表明，罕见且进行性的肺部疾病淋巴管平滑肌瘤病（LAM）本质上是转移性的。抑癌基因结节性硬化复合物（TSC），特别是 TSC2 的突变失活，会增强细胞增殖和迁移。尽管在理解 TSC2 在异常 LAM 细胞增殖及其药理学靶向中的作用方面已经取得了重大进展，但 LAM 中增强的迁移能力的机制仍未得到很好的理解。在这项研究中，我们研究了 TSC2 在细胞附着、铺展和迁移过程中的作用，这些过程有助于转移表型。在这里，我们表明 TSC2 的缺失增加了小鼠胚胎成纤维细胞对细胞外基质蛋白 I 型胶原和纤维连接蛋白的附着和铺展，而 TSC2 的重新表达则降低了这些作用。整合素-α1β1 调节细胞迁移，β1 亚基参与细胞附着和铺展，这一点通过使用功能阻断抗体得到了证明。TSC2 的缺失增加了整合素-α1 的表达，而抑制该整合素亚基则减少了细胞迁移。增强的附着和铺展与哺乳动物雷帕霉素靶蛋白复合物 1 和 Rho 相关激酶的细胞内信号通路无关，因为用雷帕霉素或 Y27632 分别进行药理学抑制没有效果。总之，这些数据表明 TSC2 通过α1β1 整合素受体控制细胞迁移、附着和铺展，因此为治疗 LAM 中细胞侵袭性增加提供了潜在的治疗靶点。
