PI3 kinase (PI3K) and tensin homolog (PTEN) lipid phosphatase control the level of cellular phosphatidylinositol (3,4,5)-trisphosphate, an activator of AKT kinase that promotes cell growth and survival. Gain-of-function mutations in PI3K and loss-of-function mutations in PTEN that activate AKT are commonly observed in human cancers. The activation of AKT causes increased protein translation and the influx of proteins into the endoplasmic reticulum (ER). The expression of ENTPD5, an ER enzyme, is up-regulated in cancer cell lines and primary human tumor samples in which AKT is activated. ENTPD5 hydrolyzes UDP in the ER to promote protein N-glycosylation and refolding. The elevation of ENTPD5 activity therefore protects AKT-active cancer cells from protein-overloading-induced ER stress and the resulting growth arrest and apoptosis.