The small GTPase Rheb in insulin and nutrient signaling

Abstract

The insulin-signaling pathway controls different aspects of cell proliferation, survival, growth and metabolism. The coordinated regulation of cell growth with the availability of nutrients is a major requirement for all eukaryotic organisms for proper development and prevention of tumor formation. This signaling network has lately received attention from the field of basic cancer research due to the increasing evidence that mutations in its components are at the base of cancer or tumor-prone syndromes. Moreover, the possibility of targeting the players in this process with anticancer drugs like rapamycin, increased the interest from the clinical point of view. The identification of Rheb as a component of the insulin pathway, acting downstream of PI3K and PKB and upstream of the ser/thr kinase mTOR, revealed the connection between these two signaling cascades. mTOR acts as master switch between anabolic and catabolic cellular processes, regulating cell growth. Its regulation by nutrient availability has been known for long, however the mechanism by which hormones like insulin and growth factors control its activity, became evident when Rheb was identified as an activator of mTOR, directly regulated by these cues.