Novel aspects of Ras proteins biology: regulation and implications

Abstract

The importance of Ras proteins as crucial crossroads in cellular signaling pathways has been well established. In spite of the elucidation of the mechanism of RAS activation by growth factors and the delineation of MAP kinase cascades, the overall framework of Ras interactions is far from being complete. Novel regulators of Ras GDP/GTP exchange have been identified that may mediate the activation of Ras in response to changes in intracellular calcium and diacylglycerol. The direct activation of Ras by free radicals such as nitric oxide also suggests potential regulation of Ras function by the cellular redox state. In addition, the array of Ras effectors continues to expand, uncovering links between Ras and other cellular signaling pathways. Ras is emerging as a dual regulator of cellular functions, playing either positive or negative roles in the regulation of proliferation and apoptosis. The signals transmitted by Ras may be modulated by other pathways triggered in parallel, resulting in the final order for proliferation or apoptosis. The diversity of ras-mediated effects may be related in part to differential involvement of Ras homologues in distinct cellular processes. The study of Ras posttranslational modifications has yielded a broad battery of inhibitors that have been envisaged as anti-cancer agents. Although an irreversible modification, Ras isoprenylation appears to be modulated by growth factors and by the activity of the isoprenoid biosynthetic pathway, which may lead to changes in Ras activity.

The cyclopentenone 15-deoxy-Δ 12,14 -prostaglandin J 2 binds to and activates H-Ras

“…Hence, a majority of Ras studies are based on the analysis of H-Ras. However, accumulating evidence supports the possibility of nonredundant roles of the three Ras homologues (25,33). The embryonic lethality seen in the Kras, but not Hras or Nras, knockout mice also provides support for this possibility (43)(44)(45)(46).…”

“…2B), thus resembling the temporal patterns of ERK2 and Akt activation by 15d-PGJ 2 . Despite their similarity, the three Ras protein homologues display specific features, including posttranslational modifications, subcellular localization, and effectiveness in the activation of different pathways (33). We then explored the behavior of H-, N-, and K-Ras proteins after treatment of cells with 15d-PGJ 2 .…”

Glutaredoxin Protects Cerebellar Granule Neurons from Dopamine-induced Apoptosis by Dual Activation of the Ras-Phosphoinositide 3-Kinase and Jun N-terminal Kinase Pathways

“…Enhancement of the DNA binding activity of NF-B protects neurons from DA-induced apoptosis (18). A survival signal pathway that might activate NF-B is the Ras/PI3K/Akt/NF-B cascade (35,36).…”

“…Enhancement of the DNA binding activity of NF-B protects neurons from DA-induced apoptosis (18). A survival signal pathway that might activate NF-B is the Ras/PI3K/Akt/NF-B cascade (35,36).Ras is a family of proteins involved in the regulation of cell proliferation, cytoskeletal rearrangements, and differentiation and survival of different cell types (37,38). Ras activation is localized on the inner surface of the cell membrane where it * This research was supported in part by Israel Science Foundation Grant 502/00-1, the Israeli Ministry of Health, Swedish Cancer Society Grant 961, and Swedish Medical Research Council Grant 03529.…”

Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002

“…44 A fatty acid moiety is added to the C terminus of Ras by farnesyl transferase (FT). Ras is thereby targeted to cell membranes, and a number of companies have developed inhibitors of the FT that leave Ras in the cytosol as an inactive enzyme.…”