Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a.
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.
Fine
Barry
B
Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
Hodakoski
Cindy
C
Koujak
Susan
S
Su
Tao
T
Saal
Lao H
LH
Maurer
Matthew
M
Hopkins
Benjamin
B
Keniry
Megan
M
Sulis
Maria Luisa
ML
Mense
Sarah
S
Hibshoosh
Hanina
H
Parsons
Ramon
R
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; C490712:PREX2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human