Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling
Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling
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DOI：
10.1038/onc.2008.219
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发表时间：
2008-10-09
期刊：
影响因子：
8
通讯作者：
Humbert, P. O.
中科院分区：
文献类型：
--
作者：
Dow, L. E.;Elsum, I. A.;Humbert, P. O.
ras -丝裂原活化蛋白激酶（MAPK）通路基因的激活突变发生在大约30%的人类癌症中；然而，仅Ras突变很少足以诱导肿瘤发展。Scribble是一种极性调节因子，最近从果蝇筛选中分离出来，用于与Ras突变合作促进肿瘤进展和细胞侵袭。在哺乳动物体内，Scribble调节定向细胞迁移和伤口愈合；然而，尚未发现哺乳动物Scribble在致癌转化中的作用。本研究表明，在表达致癌Ras或Raf的人上皮细胞中，Scribble的缺失促进了细胞通过细胞外基质在器官型培养系统中的侵袭。此外，我们表明这种情况发生的机制是Scribble对MAPK信号传导的调节。抑制MAPK信号传导是Scribble的一个高度保守的功能，因为它也可以阻止果蝇翅膀发育中raf介导的缺陷。我们的数据确定Scribble是MAPK信号传导的重要介质，并为观察Scribble在许多侵袭性人类癌症中的表达减少提供了分子基础。
Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers.