Regulation of the tumour suppressor PTEN by phosphorylation and oligomerization

肿瘤抑制因子PTEN是一种参与控制细胞生长、细胞死亡和细胞迁移的酶。PTEN被认为是一种肿瘤抑制因子，因为许多肿瘤细胞被发现携带PTEN基因突变，导致PTEN蛋白或PTEN酶活性的丧失。PTEN基因的遗传突变是一种罕见的遗传病——考登氏病的病因。考登氏症患者易患皮肤癌、甲状腺癌和乳腺癌。在实验室条件下，增加肿瘤细胞（如脑和前列腺肿瘤细胞）中PTEN的丰度可以抑制它们的生长，因此它作为肿瘤抑制因子的作用。除了作为肿瘤抑制因子，PTEN还能控制癌细胞的扩散。尽管人们对PTEN参与癌症的形成和癌细胞的扩散已经了解很多，但PTEN如何抑制肿瘤细胞的生长和扩散还不完全清楚。PTEN的酶活性增强了蛋白质中称为磷酸基团的化学基团和细胞膜中称为磷脂的脂溶性化合物的去除。PTEN抑制细胞生长和扩散的能力是由于它的酶活性。然而，PTEN的酶活性究竟是如何调控的还不清楚。为了使PTEN有效地增强对特定细胞蛋白和磷脂中磷酸基团的去除，PTEN需要位于这些蛋白和磷脂的附近。然而，PTEN究竟是如何移动到这些蛋白质和磷脂存在的位置仍然难以捉摸。本课题旨在研究细胞内PTEN酶活性和运动的调控。拟议的研究结果将揭示PTEN基因突变如何促进癌症的形成和癌细胞的扩散，并可能促进癌症治疗的研究。

The tumour suppressor PTEN is an enzyme involved in controlling cell growth, cell death, and cell migration. PTEN was identified as a tumour suppressor because many tumour cells were found to carry mutations in the PTEN gene that cause the loss of PTEN protein or the loss of PTEN enzyme activity. Hereditary mutations of the PTEN gene are the causes of a rare genetic disease called Cowden's disease. Cowden's disease patients are predisposed to developing skin, thyroid, and breast cancers. In laboratory conditions, increasing the abundance of PTEN in tumour cells such as brain and prostate tumour cells can suppress their growth, hence its role as a tumour suppressor. In addition to its role as a tumour suppressor, PTEN controls cancer cell spreading. Although much is known about the involvement of PTEN in cancer formation and the spreading of cancer cells, how PTEN suppresses tumour cell growth and spreading is not fully understood. The enzyme activity of PTEN enhances the removal of a chemical group called phosphate group from proteins and the fat-soluble compounds called phospholipids in the cell membrane. The ability of PTEN to suppress cell growth and spreading is due to its enzyme activity. However, exactly how the enzyme activity of PTEN is regulated is not well understood. In order for PTEN to efficiently enhance the removal of phosphate group from specific cellular proteins and phospholipids, PTEN needs to be located in close vicinity to these proteins and phospholipids. However, exactly how PTEN moves to the locations where these proteins and phospholipids are present remains elusive. This proposal aims at studying the regulation of PTEN enzyme activity and movement inside the cells. Results of the proposed studies will shed new light on how PTEN gene mutations contribute to cancer formation and the spreading of cancer cells and may facilitate the search for the cure of cancers.