The Ras family of proteins comprises a group of small GTPases that plays an important role in cell growth, differentiation, and survival. Ras proteins exist in an inactive, GDP-bound form and an active, GTP-bound form. Conversion of inactive GDP-Ras to active GTP-Ras is mediated by GTP exchange proteins in response to cell signaling events. GTP-Ras then promotes the activity of a wide range of effector kinases and related signaling enzymes. Hydrolysis of GTP regenerates GDP-Ras, bringing an end to the response.
Ras, a human oncogene identified and characterized over 30 y ago, is mutated in more than 20% of human cancers. Among the three Ras isoforms (K, N, and H), KRas is most frequently mutated (2). Mutant Ras has a reduced GTPase activity, which prolongs its activated conformation, thereby promoting Ras-dependent signaling and cancer cell survival or growth.
Structure of a Ras-PI3K gamma Complex

Ribbon diagram of the Ras-PI3K gamma complex. The Ras (pink helices and blue beta-sheet) and four domains of the PI3K gamma, comprising the RBD (green), C2 domain (pale green), helical domain (purple), and N- and C-terminal lobes of the catalytic domain (red and yellow) are shown. The N-terminal linker is rendered in cyan . The location of the g phosphate of the ATP PI3K gamma structure is marked with a large gray sphere. This location roughly corresponds to the phosphoinositide headgroup binding site
The Ras (pink helices and blue beta-sheet) and four domains of the PI3K gamma, comprising the RBD (green), C2 domain (pale green), helical domain (purple), and N- and C-terminal lobes of the catalytic domain (red and yellow) are shown. The N-terminal linker is rendered in cyan. A schematic of PI3K gamma domain organization is also shown.
Ribbon diagram of the Ras·PI3Kg complex. The color scheme is the same as the previous panel. The location of the g phosphate of the
ATP·PI3Kg structure is marked with a large gray sphere. This location roughly corresponds to the phosphoinositide headgroup binding site.
Because of its role in cell growth and survival, aberrant Ras signaling can contribute to carcinogenesis. In fact, mutations in RAS genes are among the most common in malignant tumors, being present in up to 30% of human cancers. Consequently, inhibitors of excessive Ras signaling are of great interest as potential cancer chemotherapeutic agents. However, attempts to discover small molecules that bind to Ras proteins and interfere with their function have met with limited success. Now the outlook is improving through the work of Vanderbilt Institute of Chemical Biology member Stephen Fesik and his laboratory, who report the discovery of small molecules that bind to the K-Ras protein and inhibit its activation [Q. Sun et al. (2012) Angew, Chem. Int. Ed., published online May 8, DOI: 10.1002/anie.201201358].
REFERENCIAS
http://www.pnas.org/content/109/14/5299.full
http://www.cell.com/action/showFullTextImages?pii=S0092-8674%2800%2900196-3
http://www.ncbi.nlm.nih.gov/pubmed/11136978?dopt=Abstract
http://www.cell.com/cell/abstract/S0092-8674(00)00196-3?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867400001963%3Fshowall%3Dtrue
http://www.vanderbilt.edu/vicb/DiscoveriesArchives/targeting_cancer_k-ras.html
Cancer Res. 1989 Sep 1;49(17):4682-9. Ras oncogenes in human cancer: a review. Bos JL1.