Akt Phosphorylation of Merlin Enhances Its Binding to Phosphatidylinositols and Inhibits the Tumor-Suppressive Activities of Merlin
Akt Phosphorylation of Merlin Enhances Its Binding to Phosphatidylinositols and Inhibits the Tumor-Suppressive Activities of Merlin
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DOI：
10.1158/0008-5472.can-08-3931
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Okada, Masashi;Wang, Yanru;Ye, Keqiang
NF 2肿瘤抑制基因编码一种称为merlin的细胞内膜相关蛋白，其属于将细胞表面糖蛋白连接到肌动蛋白细胞骨架的细胞骨架相关蛋白的带4.1家族。Merlin通过直接结合和抑制PIKE-L对PI 3 K的刺激活性来抑制磷脂酰肌醇3-激酶（PI 3 K）/Akt信号传导。Akt反馈并磷酸化merlin，引发其多聚泛素化和降解。在这里，我们表明Akt磷酸化和PI（3，4，5）P结合介导了merlin的肿瘤抑制活性。Merlin的末端NH 2直接与磷脂酰肌醇相互作用，这需要未折叠的构象。此外，Akt磷酸化增强merlin与磷脂酰肌醇的结合亲和力并抑制其促凋亡作用。此外，Akt磷酸化和磷脂酰肌醇增加merlin与CD 44的结合。表皮生长因子处理和Akt磷酸化引起merlin在皱褶质膜中聚集并促进细胞迁移。因此，这些结果表明，PI 3 K信号调节肿瘤抑制活性的梅林通过Akt磷酸化和磷脂酰肌醇脂质结合梅林。[Cancer Res 2009;69（9）：4043-51]
The NF2 tumor suppressor gene encodes an intracellular membrane-associated protein, called merlin, which belongs to the band 4.1 family of cytoskeleton-associated proteins that link cell surface glycoproteins to the actin cytoskeleton. Merlin suppresses phosphatidylinositol 3-kinase (PI3K)/Akt signaling by directly binding and inhibiting the stimulatory activity of PIKE-L on PI3K. Akt feeds back and phosphorylates merlin and provokes its polyubiquitination and degradation. Here, we show that Akt phosphorylation and PI(3,4,5)P, binding mediate the tumor-suppressive activity of merlin. The extreme NH2 terminus of merlin directly interacts with phosphatidylinositols, for which the unfolded conformation is required. Moreover, Akt phosphorylation enhances merlin binding affinity to phosphatidylinositols and inhibits its proapoptotic actions. Furthermore, Akt phosphorylation and phosphatidylinositols increase merlin binding to CD44. Epidermal growth factor treatment and Akt phosphorylation provoke merlin to aggregate in the ruffled plasma membrane and promote cell migration. Thus, these results suggest that PI3K signaling regulates the tumor-suppressive activity of merlin via both Akt phosphorylation and phosphatidylinositol lipids binding to merlin. [Cancer Res 2009;69(9):4043-51]