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 phenotypes including enhanced cellular proliferation, increased glucose metabolism, migration, and survival. We have recently determined that PREX2 is an inhibitor of PTEN phosphatase activity that is regulated by insulin and involved in the regulation of glucose metabolism. PREX2 is over expressed in human cancers with wild type PTEN. Moreover, over expression of PREX2 is seen in cancer in the presence of mutations of the gene PIK3CA encoding 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 GTPase RAC1 and is a mediator of cell migration, and we have recently demonstrated that PTEN is able to inhibit PREX2 activation of RAC1 in a PIP3-independent fashion. We propose that the mutual regulation of PTEN and PREX2 is likely to be regulated by phosphorylation based on our preliminary data. We plan to determine how this signal functions normally and is hijacked in cancer to drive proliferation and migration. This application will use a combination of biochemistry, cell biology, and mouse genetics to address the following goals: 1) to understand the mechanism of PREX2-mediated inhibition of PTEN and determine its effect on cells, 2) to understand the relationship between PTEN and PREX2 with regard to glucose metabolism, 3) to understand the mechanism through which PTEN inhibits PREX2 RAC-GEF activity and its implications for both normal cell migration and tumor cell invasion and 4) to determine the phenotypic consequences of cancer-derived PREX2 mutations and examine their basis of oncogenic action with regard to glucose metabolism, and the mutual inhibition of PTEN and PREX2.
The PI3K pathway causes the formation of cancer, and 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 mutual PTEN and PREX2 regulation that appears to be involved in the activation of the PI3K, RAC1 and glucose metabolism pathways. PREX2 represents a target for therapeutic inhibition of the PI3K and RAC1 pathways in disease.
|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|
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