Functional analysis of the relationship between the neurofibromatosis 2 tumor suppressor and its binding partner, hepatocyte growth factor-regulated tyrosine kinase substrate.
Functional analysis of the relationship between the neurofibromatosis 2 tumor suppressor and its binding partner, hepatocyte growth factor-regulated tyrosine kinase substrate.
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神经纤维瘤病 2 肿瘤抑制因子与其结合伴侣、肝细胞生长因子调节的酪氨酸激酶底物之间关系的功能分析。
DOI：
10.1093/hmg/11.25.3167
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发表时间：
2002
影响因子：
3.5
通讯作者：
Gutmann,DavidH
中科院分区：
文献类型：
--
作者：
Sun,Chun-Xiao;Haipek,Carrie;Scoles,DanielR;Pulst,StefanM;Giovannini,Marco;Komada,Masayuki;Gutmann,DavidH
患有神经纤维瘤病2（NF 2）遗传性肿瘤易感综合征的个体易于发展为神经系统肿瘤，包括神经鞘瘤和脑膜瘤。NF 2肿瘤抑制蛋白Merlin或Schwannomin抑制细胞生长和运动，并影响肌动蛋白细胞因子介导的过程。Merlin与可能介导Merlin生长抑制的几种蛋白质相互作用，包括肝细胞生长因子调节的酪氨酸激酶底物（HRS或HGS）。以前，我们证明了在RT 4大鼠神经鞘瘤细胞中HRS的调节过表达与merlin的调节过表达具有相同的功能后果。为了确定这种相互作用的功能意义，我们产生了一系列HRS截短突变体，并定义了merlin结合和HRS生长抑制所需的HRS区域。merlin结合所需的HRS结构域被缩小到含有预测的卷曲螺旋结构域的区域（残基470-497），而负责HRS生长抑制的主要结构域是不同的（残基498-550）。为了确定merlin生长抑制是否需要HRS，我们证明merlin抑制HRS +/+小鼠胚胎成纤维细胞的生长，但不抑制HRS-/-小鼠胚胎成纤维细胞的生长。相反，HRS在Nf 2表达缺失的情况下可抑制细胞生长。这些结果表明，merlin生长抑制需要HRS的表达和merlin的HRS的结合可能有助于其作为一个肿瘤抑制剂的功能。
Individuals with the neurofibromatosis 2 (NF2) inherited tumor predisposition syndrome are prone to the development of nervous system tumors, including schwannomas and meningiomas. TheNF2tumor suppressor protein, merlin or schwannomin, inhibits cell growth and motility as well as affects actin cytoskeleton-mediated processes. Merlin interacts with several proteins that might mediate merlin growth suppression, including hepatocyte growth factor-regulated tyrosine kinase substrate (HRS or HGS). Previously, we demonstrated that regulated overexpression of HRS in RT4 rat schwannoma cells had the same functional consequences as regulated overexpression of merlin. To determine the functional significance of this interaction, we generated a series of HRS truncation mutants and defined the regions of HRS required for merlin binding and HRS growth suppression. The HRS domain required for merlin binding was narrowed to a region (residues 470–497) containing the predicted coiled-coil domain whereas the major domain responsible for HRS growth suppression was distinct (residues 498–550). To determine whether merlin growth suppression required HRS, we demonstrated that merlin inhibited growth inHRS+/+, but notHRS−/−mouse embryonic fibroblast cells. In contrast, HRS could suppress cell growth in the absence ofNf2expression. These results suggest that merlin growth suppression requires HRS expression and that the binding of merlin to HRS may facilitate its ability to function as a tumor suppressor.