The lipid phosphatase activity of PTEN is critical for its tumor suppressor function
The lipid phosphatase activity of PTEN is critical for its tumor suppressor function
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DOI：
10.1073/pnas.95.23.13513
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发表时间：
1998-11-10
影响因子：
11.1
通讯作者：
Tonks, NK
中科院分区：
文献类型：
--
作者：
Myers, MP;Pass, I;Tonks, NK
自发现以来，人们推测蛋白酪氨酸磷酸酶在肿瘤抑制中发挥作用，因为它们能够拮抗促进生长的蛋白酪氨酸激酶。最近，来自人类染色体 10q23 的肿瘤抑制基因（称为 PTEN 或 MMAC1）被发现与蛋白质酪氨酸磷酸酶家族具有同源性。 PTEN 种系突变会引起几种相关的肿瘤性疾病，包括考登病。了解 PTEN 作为肿瘤抑制因子的功能的关键步骤是确定其生理底物。我在这里报告，在两个考登病家族中观察到的 PTEN 错义突变 PTEN-G129E 特异性地消除了 PTEN 识别肌醇磷脂作为底物的能力，表明脂质磷酸酶活性的丧失是导致该疾病的病因。此外，HEK293细胞中野生型或底物捕获形式的PTEN表达改变了磷脂酰肌醇3-激酶的磷脂产物的水平，并且PTEN缺陷的肿瘤细胞系中磷酸酶的异位表达导致蛋白激酶（PK）B/Akt的抑制和细胞存活的调节。
Since their discovery, protein tyrosine phosphatases have been speculated to play a role in tumor suppression because of their ability to antagonize the growth-promoting protein tyrosine kinases. Recently, a tumor suppressor from human chromosome 10q23, called PTEN or MMAC1, has been identified that shares homology with the protein tyrosine phosphatase family. Germ-line mutations in PTEN give rise to several related neoplastic disorders, including Cowden disease. A key step in understanding the function of PTEN as a tumor suppressor is to identify its physiological substrates. Here me report that a missense mutation in PTEN, PTEN-G129E, which is observed in two Cowden disease kindreds, specifically ablates the ability of PTEN to recognize inositol phospholipids as a substrate, suggesting that loss of the lipid phosphatase activity is responsible for the etiology of the disease. Furthermore, expression of wild-type or substrate-trapping forms of PTEN in HEK293 cells altered the levels of the phospholipid products of phosphatidylinositol 3-kinase and ectopic expression of the phosphatase in PTEN-deficient tumor cell lines resulted in the inhibition of protein kinase (PK) B/Akt and regulation of cell survival.