Mutual regulation of PTEN and P-REX2a in normal and cancer cells

描述(申请人提供)：PTEN是一种肿瘤抑制因子，在大量人类癌症中被解除调控，激活致癌的磷脂酰肌醇-3激酶(PI3K)途径。PTEN的失活导致多种癌症相关表型，包括增强的细胞增殖、迁移和存活。我们最近确定PREX2是PTEN磷酸酶活性的抑制因子。PREX2在野生型PTEN的人类肿瘤中高表达。此外，在编码PI3K催化亚单位的PIK3CA基因突变的癌症中，PREX2经常过度表达。我们已经证明突变体PIK3CA和PREX2在体外可以刺激细胞生长，而在野生型PTEN环境中，PREX2表达的降低抑制了肿瘤细胞的生长。PREX2编码一种酶，催化将GTP装载到小的GTP酶RAC1上，是细胞迁移和大脑正常发育的媒介。我们认为PTEN可能具有抑制通过PREX2的迁移的功能，因此，PREX2和PTEN是候选的相互抑制物。这项应用将结合生物化学、细胞生物学、小鼠遗传学和癌症生物学来解决以下目标：1)确定PREX2在体外抑制PTEN磷酸酶活性并激活细胞内PI3K途径的分子机制；2)确定PTEN和PREX2在成纤维细胞和脑中的遗传关系；3)评估PREX2在PIK3CA介导的肿瘤形成中的作用；4)确定PTEN抑制PREX2诱导的细胞迁移的机制。 公共卫生相关性：PI3K途径导致癌症的形成。对人类肿瘤的分析表明，在许多形式的人类恶性肿瘤中，它是最常见的激活途径之一。在许多情况下，癌症中的通路激活无法解释。在这里，我们将定义通过PREX2抑制PTEN的一个重要机制，它似乎是激活PI3K途径的常见机制。PREX2是治疗抑制疾病中PI3K通路的靶点。

DESCRIPTION (provided by applicant): PTEN is a tumor suppressor that is deregulated in a large number of human cancers to activate the oncogenic phosphoinositide-3 kinase (PI3K) pathway. Inactivation of PTEN leads to multiple cancer related phenotypes including enhanced cellular proliferation, migration, and survival. We have recently determined that PREX2 is an inhibitor of PTEN phosphatase activity. PREX2 is over expressed in human cancers with wild type PTEN. Moreover, PREX2 is often over expressed in cancers that harbor mutations in the PIK3CA gene, which encodes the catalytic subunit of PI3K. We have shown that mutant PIK3CA and PREX2 can stimulate cell growth in vitro, and that reduced expression of PREX2 inhibits tumor cell growth in a setting of wild type PTEN. PREX2 encodes an enzyme that catalyzes the loading of GTP onto the small GTPase RAC1 and is a mediator of cell migration and normal development in the brain. We propose that PTEN is likely to function to inhibit migration through PREX2; thus, PREX2 and PTEN are candidate mutual inhibitors. This application will use a combination of biochemistry, cell biology, mouse genetics, and cancer biology to address the following goals: 1) determine the molecular mechanism through which PREX2 inhibits PTEN phosphatase activity in vitro and activates the PI3K pathway in cells, 2) define the genetic relationships between PTEN and PREX2 in fibroblasts and the brain, 3) assess the contribution of PREX2 to PIK3CA mediated tumor formation, 4) define the mechanism through which PTEN inhibits PREX2-induced cell migration. PUBLIC HEALTH RELEVANCE: The PI3K pathway causes the formation of cancer. Analysis of human tumors has shown that it is one of the most frequently activated pathways in many forms of human malignancy. In many cases, pathway activation in cancer cannot be explained. Here we will define an important mechanism of PTEN inhibition via PREX2 that appears to be a common mechanism for activating the PI3K pathway. PREX2 represents a target for therapeutic inhibition of the PI3K pathway in disease.