Identification of a novel Ras-regulated proapoptotic pathway
Identification of a novel Ras-regulated proapoptotic pathway
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DOI：
10.1016/s0960-9822(02)00683-8
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发表时间：
2002-02-19
期刊：
影响因子：
9.2
通讯作者：
Avruch, J
中科院分区：
文献类型：
--
作者：
Khokhlatchev, A;Rabizadeh, S;Avruch, J
背景：Ras-GTPase 通过结合一系列效应分子（例如 Raf 和 PI 3-激酶）以 GTP 依赖性方式控制细胞命运决定。 NORE1 是一种非催化性多肽，可与 Ras-GTP 和其他几种 Ras 样 GTP 酶特异性结合。 NORE 与假定的肿瘤抑制因子 RASSF1 和秀丽隐杆线虫多肽 T24F1.3 同源。结果：我们发现所有三种 NORE 相关多肽都选择性地与促凋亡蛋白激酶 MST1（第 11 组 GC 激酶的成员）结合。内源性 NORE 和 MST1 在体内形成一个组成复合物，在血清刺激后与内源性 Ras 结合。通过 NORE 或肉豆蔻酰化将重组 MST1 靶向膜，增强了 MST1 的凋亡功效。组成型活性 Ki-RasG12V 的过度表达可促进多种细胞系的凋亡； Ha-RasG12V 是一种效力较弱的促凋亡剂；然而，结合 NORE 而不是 Raf 或 PI 3 激酶的 Ha-RasG12V 效应环突变体 (E37G) 表现出接近 Ki-RasG12V 的促凋亡功效。 Ki-RasG12V 和 Ha-RasG12V、E37G 的凋亡作用均受到 MST1 羧基末端非催化片段的过表达或结合 MST1 的 NORE 片段的抑制。结论：MST1 是 NORE/RASSF 多肽家族的系统发育保守伴侣，NORE-MST1 复合物是介导 NORE/RASSF 多肽家族的细胞凋亡作用的新型 Ras 效应单元。 Ki-RasG12V。
Background: The Ras-GTPase controls cell fate decisions through the binding of an array of effector molecules, such as Raf and PI 3-kinase, in a GTP-dependent manner. NORE1, a noncatalytic polypeptide, binds specifically to Ras-GTP and to several other Ras-like GTPases. NORE is homologous to the putative tumor suppressor RASSF1 and to the Caenorhabditis elegans polypeptide T24F1.3.Results: We find that all three NORE-related polypeptides bind selectively to the proapoptotic protein kinase MST1, a member of the Group 11 GC kinases. Endogenous NORE and MST1 occur in a constitutive complex in vivo that associates with endogenous Ras after serum stimulation. Targeting recombinant MST1 to the membrane, either through NORE or myristoylation, augments the apoptotic efficacy of MST1. Overexpression of constitutively active Ki-RasG12V promotes apoptosis in a variety of cell lines; Ha-RasG12V is a much less potent proapoptotic agent; however, a Ha-RasG12V effector loop mutant (E37G) that binds NORE, but not Raf or PI 3-kinase, exhibits proapoptotic efficacy approaching that of Ki-RasG12V. The apoptotic action of both Ki-RasG12V and Ha-RasG12V, E37G is suppressed by overexpression of the MST1 carboxy-terminal noncatalytic segment or by the NORE segment that binds MST1.Conclusions: MST1 is a phylogenetically conserved partner of the NORE/RASSF polypeptide family, and the NORE-MST1 complex is a novel Ras effector unit that mediates the apoptotic effect of Ki-RasG12V.