Fine Barry, Hodakoski Cindy, Koujak Susan, Su Tao, Saal Lao H, Maurer Matthew, Hopkins Benjamin, Keniry Megan, Sulis Maria Luisa, Mense Sarah, Hibshoosh Hanina, Parsons Ramon
Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
Science. 2009 Sep 4;325(5945):1261-5. doi: 10.1126/science.1173569.
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.
PTEN（第10号染色体上的磷酸酶和张力蛋白同源物）是一种肿瘤抑制因子，其细胞调控机制仍未完全明晰。我们鉴定出磷脂酰肌醇3,4,5-三磷酸RAC交换蛋白2a（P-REX2a）为一种与PTEN相互作用的蛋白。P-REX2a mRNA在人类癌细胞中更为丰富，并且在具有野生型PTEN且表达编码磷脂酰肌醇3-激酶α亚基（PI3Kα）p110亚基的PIK3CA激活突变体的肿瘤中显著增加。P-REX2a仅在存在PTEN的情况下抑制PTEN脂质磷酸酶活性并刺激PI3K途径。P-REX2a刺激细胞生长，并与PIK3CA突变体协同作用以促进不依赖生长因子的增殖和转化。在具有完整PTEN的人类细胞系中，敲低P-REX2a会减少磷酸化AKT的量并抑制细胞生长。因此，P-REX2a是PI3K途径的一个组成部分，可在癌细胞中拮抗PTEN。
