Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155117-02
Application #
8207235
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$332,000
Indirect Cost
$124,500

  Institution

Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032

  Publications

Mathur, Deepti; Stratikopoulos, Elias; Ozturk, Sait et al. (2017) PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition. Cancer Discov 7:380-390
Barrows, Douglas; He, John Z; Parsons, Ramon (2016) PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs). J Biol Chem 291:20042-54
Barrows, Douglas; Schoenfeld, Sarah M; Hodakoski, Cindy et al. (2015) p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. J Biol Chem 290:28915-31
Nguyen, H-N; Yang Jr, J-M; Rahdar, M et al. (2015) A new class of cancer-associated PTEN mutations defined by membrane translocation defects. Oncogene 34:3737-43
Mense, Sarah M; Barrows, Douglas; Hodakoski, Cindy et al. (2015) PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion. Sci Signal 8:ra32
Hodakoski, Cindy; Hopkins, Benjamin D; Barrows, Douglas et al. (2014) Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis. Proc Natl Acad Sci U S A 111:155-60
Hopkins, Benjamin D; Hodakoski, Cindy; Barrows, Douglas et al. (2014) PTEN function: the long and the short of it. Trends Biochem Sci 39:183-90
Hopkins, Benjamin D; Fine, Barry; Steinbach, Nicole et al. (2013) A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science 341:399-402
Keniry, Megan; Pires, Maira M; Mense, Sarah et al. (2013) Survival factor NFIL3 restricts FOXO-induced gene expression in cancer. Genes Dev 27:916-27
Mense, Sarah; Hodakoski, Cindy; Parsons, Ramon (2012) PREX2, a new breed of cancer gene with too many spots? Pigment Cell Melanoma Res 25:409-10

Showing the most recent 10 out of 11 publications