Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase
Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase
复制标题
DOI：
10.1038/nature04856
复制
发表时间：
2006-08-03
期刊：
影响因子：
64.8
通讯作者：
Morrison, Helen
中科院分区：
文献类型：
--
作者：
Jin, Hongchuan;Sperka, Tobias;Morrison, Helen
肿瘤抑制蛋白Merlin(由神经纤维瘤病2型基因NF2编码)是许多细胞和组织类型(1-4)中重要的增殖调节因子。Merlin通过丝氨酸518处的去磷酸化激活(S518)，这发生在血清退出或细胞-细胞或细胞-基质接触时(5，6)。然而，激活Merlin肿瘤抑制功能的相关磷酸酶尚不清楚。在此，我们将该酶确定为肌球蛋白磷酸酶(MYPT-1-PP1 Delta)。细胞内的MYPT-1-PP1增量特异性抑制剂CPI-17导致以Merlin磷酸化、RAS激活和转化为特征的Merlin功能的丧失。结构性活性的Merlin(S518A)逆转了CPI-17诱导的转化，表明Merlin是MYPT-1-PP1 Delta在肿瘤抑制中的决定性底物。此外，我们还发现在几种人类肿瘤细胞系中CPI-17的水平升高，CPI-17的下调诱导Merlin去磷酸化，抑制RAS的激活，并取消转化的表型。MYPT-1-PP1 Delta及其底物Merlin是以前未描述的肿瘤抑制级联反应的一部分，可以通过两种方式阻止，NF2基因的突变和癌蛋白CPI-17的上调。
The tumour suppressor protein merlin ( encoded by the neurofibromatosis type 2 gene NF2) is an important regulator of proliferation in many cell and tissue types(1-4). Merlin is activated by dephosphorylation at serine 518 (S518), which occurs on serum withdrawal or on cell - cell or cell - matrix contact(5,6). However, the relevant phosphatase that activates merlin's tumour suppressor function is unknown. Here we identify this enzyme as the myosin phosphatase (MYPT-1-PP1 delta). The cellular MYPT-1-PP1 delta - specific inhibitor CPI-17 causes a loss of merlin function characterized by merlin phosphorylation, Ras activation and transformation. Constitutively active merlin (S518A) reverses CPI-17-induced transformation, showing that merlin is the decisive substrate of MYPT-1-PP1 delta in tumour suppression. In addition we show that CPI-17 levels are raised in several human tumour cell lines and that the downregulation of CPI-17 induces merlin dephosphorylation, inhibits Ras activation and abolishes the transformed phenotype. MYPT-1-PP1 delta and its substrate merlin are part of a previously undescribed tumour suppressor cascade that can be hindered in two ways, by mutation of the NF2 gene and by upregulation of the oncoprotein CPI-17.