P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer

摘要: Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of plasma membrane. PIP3 recruits pleckstrin homology domain-containing proteins to membrane activate oncogenic signaling cascades. Anticancer therapeutics targeting PI3K/AKT/mTOR (mammalian target rapamycin) pathway are clinical development. In a mass spectrometric screen identify PIP3-regulated breast cells, levels Rac activator PIP3-dependent exchange factor-1 (P-REX1) increased response PI3K inhibition, decreased upon loss antagonist phosphatase tensin homolog (PTEN). P-REX1 mRNA protein were positively correlated with ER expression, inversely activation tumors as assessed gene expression phosphoproteomic analyses. Rac1, PI3K/AKT MEK/ERK PTEN-independent manner, promoted tumor viability. Loss or inhibition suppressed MEK/ERK, also insulin-like receptor activation, suggesting that provides positive feedback activators upstream PI3K. support model where PIP3-driven both signaling, high (but not phospho-AKT transcriptomic signature activation) predictive sensitivity inhibitors among lines. was highest estrogen receptor-positive compared many other subtypes, neutralizing P-REX1/Rac axis may provide novel therapeutic approach selectively abrogate cells.