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Science 325 (5945): 1261-1265

Copyright © 2009 by the American Association for the Advancement of Science

Activation of the PI3K Pathway in Cancer Through Inhibition of PTEN by Exchange Factor P-REX2a

Barry Fine,1 Cindy Hodakoski,1 Susan Koujak,1 Tao Su,1,2 Lao H. Saal,1 Matthew Maurer,1,4 Benjamin Hopkins,1 Megan Keniry,1 Maria Luisa Sulis,1,3 Sarah Mense,1 Hanina Hibshoosh,1,2 Ramon Parsons1,2,4,*

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} (PI3K{alpha}). 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.

1 Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
2 Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.
3 Division of Pediatric Oncology, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.
4 Department of Medicine, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: rep15{at}columbia.edu


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