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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Progression and Metastasis Study Section (TPM)
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Jhappan, Chamelli
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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