21 - Ras

Summary

Ras

First identified in transforming retroviruses, Ras proteins are GTP/GDP-binding molecular switches and the founding members of the Ras superfamily of small GTPases (1,2). They serve as key signaling nodes mediating many aspects of normal cell physiology, such as mitogen-stimulated growth, differentiation and death/survival, and are the most frequently mutated oncogenes in human cancers. The activity of Ras proteins is regulated by a cycle of binding to guanine nucleotides, where the GDP-bound protein is in the resting state, and the GTP-bound protein is in the active form (Figure 21.1). Activation is induced by positive regulators called guanine nucleotide exchange factors (GEFs) that promote dissociation of the bound GDP. Due to the high intra-cellular concentrations of GTP, this dissociation results in the exchange of GDP for GTP. Once bound to GTP, Ras assumes a conformation that promotes binding to its downstream effector proteins and subsequent transmission of signals that produce its biological effects. Normal Ras signaling is then rapidly turned off by the action of negative regulatory GTPase activating proteins (GAPs) that accelerate the otherwise slow rate of intrinsic hydrolysis of the bound GTP to GDP, thereby restoring the resting GDP-bound conformation. Ras proteins that are resistant to GAP activity are constitutively GTP-bound and active. Mutational activation of RAS that causes the protein to be GAP-resistant is the most common mechanism of RAS-mediated oncogenesis. The three RAS genes, HRAS, KRAS, and NRAS, specify four ~21 kDa Ras proteins, with alternative splicing of the fourth exon of KRAS resulting in expression of K-Ras4A and K-Ras4B proteins. The Ras isoforms are not fully inter-changeable. In addition to GTP-binding, all Ras proteins require modification by farnesyl isoprenoids at their C-terminal CAAX motifs for their subcellular localization and biological activity; the four isoforms vary in the additional post-translational modifications that are signaled by their distinct C-terminal membrane-targeting domains. These distinctions play a large role in determining the specific spatiotemporal regulation and biological consequences of both wild-type and oncogenic forms of Ras. Although the particular RAS isoform and residue vary among cancer types, missense mutations in KRAS at G12 are by far the most frequent, especially in cancers of the pancreas, colon, and lung, followed by NRAS Q61 mutations, especially in hematopoietic diseases and melanomas; HRAS is rarely mutated.