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Regulating the regulator: post-translational modification of RAS
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Journal Article
Regulating the regulator: post-translational modification of RAS
2012
Overview
Key Points
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).
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.
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.
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.
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.
Monoubiquitylation and diubiquitylation of HRAS regulate its association with endosomes, and monoubiquitylation of KRAS4B enhances its activation.
S
-nitrosylation of Cys118 of RAS promotes guanine nucleotide exchange.
Toxins produced by
Pseudomonas aeruginosa
and
Clostridium sordelli
ADP-ribosylate and monglucosylate RAS, respectively, leading to diminished signalling.
RAS proteins are monomeric GTPases that act as binary molecular switches to regulate a wide range of cellular processes. Their trafficking and activity are regulated by constitutive post-translational modifications (PTMs), including farnesylation, methylation and palmitoylation, as well as conditional PTMs, such as phosphorylation, peptidyl-proly isomerization, ubiquitylation, nitrosylation, ADP ribosylation and glucosylation.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
