Abstract
PTEN (phosphatase and tensin homolog on chromosome 10) is a tumor suppressor whose cellular regulation remains incompletely understood. We identified phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (P-REX2a) as a PTEN-interacting protein. P-REX2a mRNA was more abundant in human cancer cells and significantly increased in tumors with wild-type PTEN that expressed an activated mutant of PIK3CA encoding the p110 subunit of phosphoinositide 3-kinase subunit alpha (PI3Kalpha). P-REX2a inhibited PTEN lipid phosphatase activity and stimulated the PI3K pathway only in the presence of PTEN. P-REX2a stimulated cell growth and cooperated with a PIK3CA mutant to promote growth factor-independent proliferation and transformation. Depletion of P-REX2a reduced amounts of phosphorylated AKT and growth in human cell lines with intact PTEN. Thus, P-REX2a is a component of the PI3K pathway that can antagonize PTEN in cancer cells.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism
-
Breast Neoplasms / pathology
-
Cell Line
-
Cell Line, Tumor
-
Cell Proliferation
-
Female
-
GTPase-Activating Proteins / genetics
-
GTPase-Activating Proteins / metabolism*
-
Guanine Nucleotide Exchange Factors
-
Humans
-
Male
-
Mutation
-
Neoplasms / genetics
-
Neoplasms / metabolism*
-
Neoplasms / pathology
-
PTEN Phosphohydrolase / antagonists & inhibitors*
-
PTEN Phosphohydrolase / chemistry
-
PTEN Phosphohydrolase / genetics
-
PTEN Phosphohydrolase / metabolism*
-
Phosphatidylinositol 3-Kinases / metabolism*
-
Phosphorylation
-
Protein Binding
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins c-akt / metabolism
-
Signal Transduction
Substances
-
GTPase-Activating Proteins
-
Guanine Nucleotide Exchange Factors
-
PREX2 protein, human
-
Phosphatidylinositol 3-Kinases
-
Proto-Oncogene Proteins c-akt
-
PTEN Phosphohydrolase
-
PTEN protein, human