Melanoma Molecular Maps Projects



Title: G proteins and the RAS superfamily
Legend: Guanine nucleotide-binding proteins (G proteins) transduce extracellular signals into intracellular changes through second-messenger cascades. G proteins include the heterotrimeric G proteins (large G proteins) that are activated by membrane G-protein-coupled receptors (GPCR) and the monomeric small G proteins (also referred to as small GTPases). Of the small G proteins, the RAS superfamily of GTPases is the most studied and comprises over one hundred small (20-40 kDa) monomeric G proteins. The RAS superfamily is classified into five major subfamilies: RAS, RHO, RAB, RAN and ARF. These proteins function as regulators of important biological processes, including transmembrane signal transduction (RAS), cytoskeletal reorganization (RHO), gene expression (RAS, RHO), intracellular vesicle trafficking (RAB, ARF), microtubule organization (RAN) and nucleocytoplasmic transport (RAN). Despite their functional and structural diversity, they all possess GDP/GTP-binding and intrinsic GTPase activities that enable them to switch between biologically active (GTP-bound) and inactive (GDP-bound) conformations. Each cycle of activation and inactivation is coupled with the transduction of an upstream signal to downstream effectors. The role of the RAS superfamily of GTPases in carcinogenesis is well established. Mutational activation of the RAS subfamily occurs in about 20% of human cancers; members of the RAS subfamily that have been reported to be mutated in different types of cancer include KRAS in pancreatic cancer, non-small-cell lung cancer, colorectal cancer and seminoma; NRAS in melanoma, hepatocellular cancer, myelodysplastic syndrome and acute myelogenous leukaemia; and HRAS in follicular and undifferentiated papillary thyroid cancer, bladder cancer and renal cell cancer. All these mutations stabilize RAS in a constitutively active GTP-bound conformation. REFERENCES: [1] Shaw RJ et al, Nature 2006, 441:424-30. [2] Schubbert S et al, Nat Rev Cancer 2007, 7:295-308. Figure #15
Author: The MMMP Team (updated: August 2008)

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