Ras/PI3K pathway activation is required for Ad36-induced cellular glucose uptake. These findings are potentially highly significant for developing new treatment approaches for type 2 diabetes and insulin resistance. Particularly, the AbMole L-701324 unique capability of Ad36 to attenuate hyperglycemia despite a continued HF-diet and without a reduction in visceral or subcutaneous adiposity offers a remarkable opportunity to creatively negate the hyperglycemic effects of excess adiposity or dietary fat intake, without the need to reduce it. However, for developing a therapeutic approach, infection with a virus is impractical. Instead, a viral AbMole Scopoletin protein that is responsible for the effect could provide a drug ligand or a target. Here we show that E4orf1 is required to mediate the glucose uptake induced by Ad36. Also, E4orf1 is sufficient to promote glucose uptake in preadipocytes, adipocytes, and myoblasts, and to reduce glucose output by hepatocytes. Ad9 E4orf1, which is 96% homologous to Ad36 E4orf1, mediates Ras activation by complexing with Dlg1 via its PBM, which also appears to be the case with Ad36 E4orf1. Ad36 E4orf1 activates Ras and PI3K, the two main signaling components required for Ad36 infection-induced glucose disposal. Ad36 E4orf1 requires its PBM for activating Ras and for upregulating glucose uptake. Specifically, Ad36 E4orf1 increases the relative abundance and activation of H-Ras isoform. E4orf1 appears to activate Ras, to induce the distal insulin signaling pathway. Ras, an important GTP binding protein,, has been recognized to induce PI3K/AKT pathway, or mimic insulin action on glucose transporters Glut4 and Glut1. In a mouse model, transgenic overexpression of H-Ras in adipose tissue increased insulin sensitivity, and up-regulated adipose tissue Glut4 and Glut1 and glucose uptake even in absence of insulin. Ras-induced glucose disposal was ignored since it plays a negligible role in insulin-stimulated glucose uptake. Conversely, Ras/PI3K pathway may be very valuable as an alternate pathway to promote cellular glucose disposal, if insulin signaling is impaired. In the absence of functional insulin signaling as in type 2 diabetes or obesity, an agent such as E4orf1 that up-regulates insulin independent glucose disposal through Ras activation may be valuable. Very recently, Ras seems to re-attract attention for its insulin-independent effects on glucose metabolism. Future experiments that knockdown Ras will determine if, like Ad36, its E4orf1 protein also ��requires�� Ras for promoting glucose disposal. These data provide important information needed to design ligands and therapeutic targets for improving glycemic control. Although Ras is known as an oncogene, its activation alone is not sufficient to induce tumor formation. For instance, dysregulated focal adhesion kinase is necessary for Ras activation to result in cell transformation.