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

描述（由申请人提供）：PTEN是一种肿瘤抑制因子，在大量人类癌症中被解除调控，以激活致癌磷酸肌醇-3激酶（PI3K）途径。PTEN失活导致多种癌症相关表型，包括细胞增殖、迁移和存活增强。我们最近确定PREX2是PTEN磷酸酶活性的抑制剂。PREX2在野生型PTEN的人类肿瘤中过表达。此外，PREX2经常在PIK3CA基因突变的癌症中过度表达，PIK3CA基因编码PI3K的催化亚基。我们已经证明突变体PIK3CA和PREX2可以刺激体外细胞生长，在野生型PTEN环境下，PREX2的表达降低可以抑制肿瘤细胞的生长。PREX2编码一种酶，该酶催化GTP装载到小GTP酶RAC1上，并且是大脑细胞迁移和正常发育的介质。我们认为PTEN可能通过PREX2抑制迁移；因此，PREX2和PTEN是候选的相互抑制剂。该应用程序将使用生物化学，细胞生物学，小鼠遗传学和癌症生物学的组合来解决以下目标：1)确定PREX2体外抑制PTEN磷酸酶活性并激活细胞内PI3K通路的分子机制；2)确定成纤维细胞和大脑中PTEN和PREX2的遗传关系；3)评估PREX2对PIK3CA介导的肿瘤形成的贡献；4)确定PTEN抑制PREX2诱导的细胞迁移的机制。

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.