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PMID: 19729658 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a.

Science (New York, N.Y.) ·Vol. 325 ·No. 5945 ·2009-09-04 ·Pages 1261-5

Fine B, Hodakoski C, Koujak S, Su T, Saal LH, Maurer M, Hopkins B, Keniry M, Sulis ML, Mense S, Hibshoosh H, Parsons R

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.

MeSH Terms
Breast Neoplasms/genetics,metabolism,pathology Cell Line Cell Line, Tumor Cell Proliferation Female GTPase-Activating Proteins/genetics,metabolism Guanine Nucleotide Exchange Factors Humans Male Mutation Neoplasms/genetics,metabolism,pathology PTEN Phosphohydrolase/antagonists & inhibitors,chemistry,genetics,metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins c-akt/metabolism Signal Transduction
Chemicals
GTPase-Activating Proteins Guanine Nucleotide Exchange Factors PREX2 protein, human Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase PTEN protein, human
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Fine Barry
Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
Hodakoski Cindy
Koujak Susan
Su Tao
Saal Lao H
Maurer Matthew
Hopkins Benjamin
Keniry Megan
Sulis Maria Luisa
Mense Sarah
Hibshoosh Hanina
Parsons Ramon
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1173569
Published
2009-09-04
Pages
1261-5
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC2936784
Subset
IM
Grants
NCI NIH HHS · P01 CA097403-06A1 · United States
NCI NIH HHS · P01 CA097403 · United States
NCI NIH HHS · P01 CA097403-01A10003 · United States
NCI NIH HHS · R01 CA082783-10 · United States
NCI NIH HHS · R01 CA082783-07 · United States
NCI NIH HHS · R01 CA082783-06 · United States
NCI NIH HHS · R01 CA082783-08 · United States
NCI NIH HHS · CA097403 · United States
NCI NIH HHS · R01 CA082783 · United States
NCI NIH HHS · R01 CA082783-09 · United States
External Links
PubMed source DOI: 10.1126/science.1173569 PMC Full Text View journal details
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