Key Points
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RAS proteins are molecular switches that regulate a wide range of signalling pathways by engaging effectors on cellular membranes. They are themselves regulated by various post-translational modifications (PTMs).
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RAS proteins associate with membranes by virtue of a series of constitutive PTMs of their carboxy-terminal CAAX sequence. These PTMs include prenylation, proteolysis and carboxyl methylation.
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Membrane association and trafficking of all RAS isoforms other than KRAS4B are also regulated by the reversible palmitoylation of Cys residues in the C-terminal hypervariable regions of the proteins.
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Cis–trans isomerization of a peptidyl-prolyl bond adjacent to a palmitate in HRAS acts as a molecular timer that regulates depalmitoylation and retrograde trafficking.
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Phosphorylation of KRAS4B in its polybasic region allows this protein to dissociate from the plasma membrane through a mechanism known as the farnesyl–electrostatic switch.
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Monoubiquitylation and diubiquitylation of HRAS regulate its association with endosomes, and monoubiquitylation of KRAS4B enhances its activation.
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S-nitrosylation of Cys118 of RAS promotes guanine nucleotide exchange.
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Toxins produced by Pseudomonas aeruginosa and Clostridium sordelli ADP-ribosylate and monglucosylate RAS, respectively, leading to diminished signalling.
Abstract
RAS proteins are monomeric GTPases that act as binary molecular switches to regulate a wide range of cellular processes. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which regulate the activation state of RAS without covalently modifying it. By contrast, post-translational modifications (PTMs) of RAS proteins direct them to various cellular membranes and, in some cases, modulate GTP–GDP exchange. Important RAS PTMs include the constitutive and irreversible remodelling of its carboxy-terminal CAAX motif by farnesylation, proteolysis and methylation, reversible palmitoylation, and conditional modifications, including phosphorylation, peptidyl-prolyl isomerisation, monoubiquitylation, diubiquitylation, nitrosylation, ADP ribosylation and glucosylation.
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Glossary
- Costello syndrome
-
A rare genetic disorder, similar to Noonan syndrome and cardio-facial-cutaneous syndrome, that is caused by an activating mutation in the gene encoding HRAS.
- Noonan syndrome
-
An autosomal-dominant congenital disease that results in various developmental defects, including, but not limited to, dwarfism, pulmonary valve stenosis and learning disabilities. More than half of the cases are caused by mutations in the gene encoding SHP2 and the others include gain-of-function mutations in the genes for KRAS or Son of sevenless homologue 1, placing Noonan syndrome in the RASopathy category.
- Cardio-facio-cutaneous syndrome
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A rare genetic disorder that is characterized by a distinctive facial appearance, congenital cardiac malformations and learning difficulties. Like Noonan syndrome, it is a RASopathy caused by gain-of-function mutations, but in this case in the genes encoding KRAS, BRAF or MAPK/ERK kinase (MEK).
- Nitrosylation
-
The modification of a Cys side chain sulphhydryl group with a nitrosyl group derived from nitric oxide.
- G domain
-
The first 169 amino acids of RAS proteins, which fold into a globular, hydrophilic protein that contains a guanine-nucleotide (G)-binding site.
- Heterotrimeric G proteins
-
Members of the large subfamily of guanine-nucleotide-binding proteins that signal downstream of receptors that span the plasma membrane seven times. Composed of three subunits designated α, β and γ, of which the α-subunit binds nucleotide.
- SH2 domain
-
(SRC homology 2 domain). One of several types of domain found in numerous signalling molecules that bind to phosphotyrosine in the context of adjacent amino acids.
- Cis–trans isomerization
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Transformation, usually by an enzyme, of a peptide bond, or more commonly a peptidyl-prolyl bond, from a cis to a trans conformation or vice versa.
- Myristoyl–electrostatic switch
-
A term used to describe the mechanism whereby the membrane association of N-myristoylated proteins, such as myristoylated Ala-rich C-kinase substrate (MARCKS), is modulated by phosphorylation of Ser residues in an adjacent polybasic region.
- Polytopic membrane proteins
-
Transmembrane proteins that span cellular membranes multiple times.
- Early endosomes
-
Dynamic tubulovesicular organelles that form from the uncoating and fusing of clathrin-coated vesicles and represent the earliest element of the endocytic cycle.
- Late endosomes
-
Non-tubular organelles that mature from early endosomes, are partially acidified and fuse with primary lysosomes.
- Multivesicular bodies
-
Late endosomes into which vesicles have budded off to form a cluster of smaller vesicles within the larger endosome.
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Ahearn, I., Haigis, K., Bar-Sagi, D. et al. Regulating the regulator: post-translational modification of RAS. Nat Rev Mol Cell Biol 13, 39–51 (2012). https://doi.org/10.1038/nrm3255
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DOI: https://doi.org/10.1038/nrm3255
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