RAS subfamily: Introduction

Over 150 human Ras proteins (small guanosine triphosphatases (GTPases)) have been reported in the literature which are divided into 5 subfamilies (RAS, Rho, Rab, Ran and Arf subfamilies) based on structural and functional homology (reviewed in [9]). The oncogenes, HRAS, KRAS and NRAS are three archetypal members of this protein superfamily.

Ras family proteins are critical for intracellular signalling through pathways that control essential cellular processes such as actin cytoskeletal integrity, cell adhesion, migration, differentiation, proliferation, and apoptosis. Ras proteins function as on/off switches for signal transduction. Activation of RAS is controlled by cycling between the active GTP-bound and inactive GDP-bound conformations. RAS proteins have intrinsic GTPase activity and can hydrolyse GTP to GDP, but this is augmented by interaction with guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs act to release GDP from Ras proteins leading to activation via binding of more GTP from the cytoplasm, and GAPs act to accelerate RAS inactivation. The balance between GEF and GAP activity is therefore important for the control of Ras signalling. Fine tuning of Ras-controlled signalling is achieved through variations in post-translational modifications which target different Ras proteins to specific subcellular locations where discrete pools of regulators and effectors dictate overall Ras activity.

Upregluated Ras protein activity, either as a result of activating mutations or growth factor stimulation, has been reported in many types of cancer [2,6], where it causes increased invasion and metstasis and reduced levels of apoptosis [4]. It is estimated that Ras signaling is abnormally activated in one-third of human cancers, including cancers of the pancreas, colon, lung and breast. The N-RAS gene is mutated in up to 30% of acute myeloid leukemias (AML) [4]. Commonly found somatic point mutations include those affecting codons for amino acids at positions 12, 13, 61, or 113–117. Mutations often disrupt the hydrolytic site of the protein, which results in the protein being locked in the GTP-bound active state. For this reason Ras inhibitors are being investigated by the pharmaceutical industry as potential anticancer therapies [1,5]. Salirasib (farnesylthiosalicylic acid) is one investigational small molecule which inhibits Ras activity by interfering with its membrane attachment, thereby disrupting its subcellular localisation [8]. The action of salirasib has potent effects on cancer cells [3]. More recently, small molecules which act as allosteric inhibitors of oncogenic KRAS have been identified [7].


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1. Baines AT, Xu D, Der CJ. (2011) Inhibition of Ras for cancer treatment: the search continues. Future Med Chem, 3 (14): 1787-808. [PMID:22004085]

2. Bezniakow N, Gos M, Obersztyn E. (2014) The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes. Dev Period Med, 18 (3): 285-96. [PMID:25182392]

3. Blum R, Jacob-Hirsch J, Amariglio N, Rechavi G, Kloog Y. (2005) Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death. Cancer Res, 65 (3): 999-1006. [PMID:15705901]

4. Bos JL. (1989) ras oncogenes in human cancer: a review. Cancer Res, 49 (17): 4682-9. [PMID:2547513]

5. Ebi H, Faber AC, Engelman JA, Yano S. (2014) Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers. Cancer Sci, 105 (5): 499-505. [PMID:24612015]

6. Goitre L, Trapani E, Trabalzini L, Retta SF. (2014) The Ras superfamily of small GTPases: the unlocked secrets. Methods Mol Biol, 1120: 1-18. [PMID:24470015]

7. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503 (7477): 548-51. [PMID:24256730]

8. Rotblat B, Ehrlich M, Haklai R, Kloog Y. (2008) The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: a potential treatment for cancer. Meth Enzymol, 439: 467-89. [PMID:18374183]

9. Wennerberg K, Rossman KL, Der CJ. (2005) The Ras superfamily at a glance. J Cell Sci, 118 (Pt 5): 843-6. [PMID:15731001]

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