Regulation of PTEN Activity in Cancer Cells

癌细胞中 PTEN 活性的调节

• 批准号: 6764253
• 负责人: Emmanuelle Joelle Meuillet
• 金额: $ 29.97万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764253
• 关键词: Drosophilidae; biological signal transduction; genetic regulation; intermolecular interaction; molecular oncology; neoplastic cell; phosphomonoesterases; protein localization; protein protein interaction; protein structure function; protein transport; selenium; thioredoxin; tissue /cell culture; tumor suppressor proteins

DESCRIPTION (provided by applicant): Regulation of PTEN activity and translocation in normal and cancer cells. PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a recently identified tumor suppressor, which is deleted/mutated in human tumors including glioblastomas, carcinomas of the prostate, uterus, bladder and breast and malignant melanomas. PTEN dephosphorylates the 3-position of phosphatidylinositol (Pdtlns)-3-phosphates, thus, preventing activation of Akt by Ptdlns-3-kinase. PTEN also dephosphorylates focal adhesion kinase (p125FAK) and Shc, a SH2-phosphotyrosine-binding adapter protein that links tyrosine kinases to Ras signaling and the MAP kinase pathway. PTEN contains a C2 lipid binding domain at its C-terminal end, which is responsible for its' binding to phosphatidylcholine at the inner leaflet of the plasma membrane in a Ca2+-independent manner. It has been suggested that this domain may influence the activity of the protein, but no clear-cut role for the C2 domain of PTEN has been proposed.We have recently found that a small redox protein, thioredoxin, binds directly to the C2 domain of PTEN and thereby is able to negatively regulate the lipid activity of PTEN. Thioredoxin binds to the Cys212 of PTEN forming a stable complex, which can be regulated in a redox dependent manner. Moreover, the addition of selenium to cells, which is know to increase thioredoxin reductase activity, is able to restore PTEN activity.Hence, the hypotheses upon which our studies are based are that 1) PTEN activity is allosterically regulated by a small redox protein and indirectly by selenium and that 2) PTEN activity can be regulated indirectly by its C2 domain. The objectives of our proposed studies are directed towards a better understanding of the role of the C2 domain in the translocation of PTEN and in the regulation of the activity of PTEN via its interaction with other proteins.

描述（由申请人提供）：正常和癌细胞中PTEN活性和易位的调节。 PTEN（染色体上的磷酸酶和TENSIN同源物在染色体上删除）是最近鉴定出的肿瘤抑制剂，在包括胶质母细胞瘤，前列腺癌，子宫，膀胱，膀胱和乳腺癌和乳腺癌和恶性黑素瘤在内的人类肿瘤中被删除/突变。 PTEN脱磷酸化磷脂酰肌醇（PDTLNS）-3-磷酸盐的3位，从而防止PTDLNS-3-激酶阻止AKT激活。 PTEN还可以去磷酸化粘附激酶（P125FAK）和SHC，SHC是SH2-磷酸酪氨酸结合衔接蛋白，将酪氨酸激酶与RAS信号和MAP激酶途径联系起来。 PTEN在其C末端包含一个C2脂质结合结构域，该结构域的原因是其与质膜内部小叶的磷脂酰胆碱的结合，并以Ca2+非依赖性方式结合。已经提出，该结构域可能会影响蛋白质的活性，但已经提出了PTEN的C2结构域的明确作用。我们最近发现，一种小的氧化还原蛋白硫氧还蛋白直接与PTEN的C2结构结合，因此可以负调节PTEN的脂质活性。硫氧还蛋白与PTEN形成稳定复合物的PTEN的Cys212结合，可以以氧化还原依赖的方式调节。此外，将硒添加到细胞中，知道可以增加硫氧还蛋白还原酶活性，能够恢复PTEN活性。因此，我们的研究所基于的假设是1）PTEN活性在小型氧化还原蛋白上被构成小的氧化还原蛋白，并通过硒而受到selenium和2）PTEN活性的c2 domains andirectirecect and c2 domains。我们提出的研究的目标是针对更好地理解C2结构域在PTEN易位和PTEN通过与其他蛋白质的相互作用来调节活动中的作用。