Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylationmimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach. M embers of the rat sarcoma (RAS) family of small monomeric GTPases function as molecular binary switches, with their biological activities determined by their nucleotide-binding state. When bound to GTP, RAS proteins engage a variety of downstream "effector" pathways to influence cellular behavior (1). As such, the nucleotide-binding state of RAS must be highly regulated in a cell, and this regulation is accomplished through the activity of positive and negative cofactors. Wild-type RAS has low intrinsic GTPase activity and thus relies on GTPaseactivating proteins (GAPs) to hydrolyze GTP efficiently. Guanine nucleotide exchange factors (GEFs) facilitate the reloading of GDP-bound RAS with GTP. Activating-point mutations in RAS proteins are common in cancer, with missense mutations at codons 12 and 13 being the most prevalent (2). These particular mutations affect the endogenous enzymatic activity of RAS, but have a much greater effect on GAP-induced GTP hydrolysis, effectively shifting the nucleotide-binding equilibrium of RAS toward its constitutively active (i.e., GTP-bound) state (3).The nucleotide-binding state affects RAS activity by influencing its 3D structure. When RAS binds to GTP, it undergoes a conformational change that primarily affects two regions of the protein: Switch I, which binds to effectors and GAPs, and Switch II, which is critical for GEF and GAP activity and for interaction with PI3K (4-7). Mutations that impinge on the nucleotide-dependent conformation change affect the ability of RAS to release nucleotide in the presence of GEF and to activate downstream effectors (8). In essence, proper RAS function requires the ability to cycle between its active and inactive conformations.Within a cell, RAS proteins must associate with cellular membranes to transmit signals to downstream effector proteins. Because RAS itself is not a transmembrane protein, its proper localization is accomplished through posttranslational lipidation, primarily by irreversible farnesylation o...
Activating point mutations in K-RAS are extremely common in cancers of the lung, colon, and pancreas and are highly predictive of poor therapeutic response. One potential strategy for overcoming the deleterious effects of mutant K-RAS is to alter its post-translational modification. While therapies targeting farnesylation have been explored, and ultimately failed, the therapeutic potential of targeting other modifications remains to be seen. We recently demonstrated that acetylation of lysine 104 attenuates K-RAS transforming activity by interfering with GEF-induced nucleotide exchange. Here, we have identified HDAC6 and SIRT2 as deacetylases that regulate the acetylation state of K-RAS in cancer cells. By extension, inhibition of either of these enzymes dramatically affects the growth properties of cancer cell lines expressing mutationally activated K-RAS. These results suggest that therapeutic targeting of HDAC6 and/or SIRT2 may represent a new way to treat cancers expressing mutant forms of K-RAS.
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