Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Point mutations of several amino acids of human RAS, including gly12, ala59, or glu63, render the protein constitutively active. Embryonic stem cell-expressed Ras (ERAS) has serine, alanine, and asparagine at the positions corresponding to gly12, ala59, and glu63 of human RAS, suggesting that it is constitutively active.The PI3K (phosphoinositide 3-kinase) pathway is important for proliferation, survival and maintenance of pluripotency in ES cells. The PI3K pathway is activated by growth factors and cytokines including insulin and leukaemia inhibitory factor. In addition to these exogenous factors, the PI3K pathway is endogenously activated by the constitutively active Ras family protein ERas (ES cell-expressed Ras). ERas null ES cells maintained pluripotency but show significantly reduced growth and tumorigenicity, which can be rescued by expression of ERas cDNA or by activated phosphatidylinositol 3-hydroxykinase. The transforming oncogene ERAS appears to be important in the tumor-like growth properties of ES cells.