Regulating the regulator: post-translational modification of RAS

Ahearn, Ian M.; Haigis, Kevin M.; Bar–Sagi, Dafna; Philips, Mark R.

doi:10.1038/nrm3255

Cited by 477 publications

(440 citation statements)

References 143 publications

Supporting

Mentioning

427

Contrasting

Unclassified

Order By: Relevance

“…HRasGDP and N-RasGTP allosteric lobe residues are poised to interact primarily with cholesterol and sphingomyelin, whereas H-RasGTP and N-RasGDP residues should interact with unsaturated phospholipids, including PtdCho, PtdSer, and PtdIns. The polybasic region of K-Ras containing 6 consecutive lysine residues facilitates correct trafficking and localization to the plasma membrane (12). Because the farnesyl group cannot insert as deeply into the membrane as the palmitoylate group, the K-Ras-membrane interaction is stabilized through nonspecific electrostatics (22,31), similar to the other membrane-bound Ras GTPase super family members Rac-1 and MARCKS (32,33).…”

Section: Ras Isoform Microlocalization In the Plasma Membranementioning

confidence: 92%

“…After -AAX removal, each isoform is farnesylated at Cys186 to promote weak membrane binding, whereas a secondary motif enhances the membrane association and defines isoform-specific trafficking and microlocalization patterns (7). The secondary motif consists of two palmitoyl groups on H-Ras (Cys181 and Cys184), a single palmitoyl on N-Ras (Cys181), and a hexalysine polybasic region (residues 175-180) for K-Ras (12). The details of Ras acylation have been reviewed elsewhere (7).…”

Section: C-terminal Posttranslational Modifications Govern the Ras-mementioning

confidence: 99%

“…Ubiquitinylation also regulates spatial-temporal Ras signaling output. Endosomal enrichment is achieved via H-Ras ubiquitinylation, whereas K-Ras monoubiquitinylation increases GTP loading in concert with a G12V mutation to amplify interaction with Raf and PI3K (12).…”

Section: C-terminal Posttranslational Modifications Govern the Ras-mementioning

confidence: 99%

See 2 more Smart Citations

The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain

Parker

Mattos

2015

Molecular Cancer Research

View full text Add to dashboard Cite

The small GTPase Ras is mutated in about 20% of human cancers, primarily at active site amino acid residues G12, G13, and Q61. Thus, structural biology research has focused on the active site, impairment of GTP hydrolysis by oncogenic mutants, and characterization of protein-protein interactions in the effector lobe half of the protein. The C-terminal hypervariable region has increasingly gained attention due to its importance in H-Ras, N-Ras, and K-Ras differences in membrane association. A highresolution molecular view of the Ras-membrane interaction involving the allosteric lobe of the catalytic domain has lagged behind, although evidence suggests that it contributes to isoform specificity. The allosteric lobe has recently gained interest for harboring potential sites for more selective targeting of this elusive "undruggable" protein. The present review reveals critical insight that isoform-specific differences appear prominently at these potentially targetable sites and integrates these differences with knowledge of Ras plasma membrane localization, with the intent to better understand the structure-function relationships needed to design isoform-specific Ras inhibitors. Mol Cancer Res; 13(4); 595-603. Ó2015 AACR.

show abstract

Section: Ras Isoform Microlocalization In the Plasma Membranementioning

confidence: 92%

Section: C-terminal Posttranslational Modifications Govern the Ras-mementioning

confidence: 99%

See 1 more Smart Citation

The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain

Parker

Mattos

2015

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…The best-studied examples are probably the two small GTPase isoforms H-and N-Ras, members of the proto-oncogene family that shuttle between the Golgi apparatus and the plasma membrane (PM) to regulate activity and signalling (Ahearn et al, 2012). Concomitantly, the enzymes responsible for palmitoylation and depalmitoylation have been associated with important human diseases and cancers (Greaves and Chamberlain, 2011;Resh, 2012).…”

Section: Acylation Impacts On the Fate Of Proteinsmentioning

confidence: 99%

Emerging roles for protein S-palmitoylation in Toxoplasma biology

Frénal

Kemp

Soldati‐Favre

2014

International Journal for Parasitology

View full text Add to dashboard Cite

a b s t r a c tPost-translational modifications are refined, rapidly responsive and powerful ways to modulate protein function. Among post-translational modifications, acylation is now emerging as a widespread modification exploited by eukaryotes, bacteria and viruses to control biological processes. Protein palmitoylation involves the attachment of palmitic acid, also known as hexadecanoic acid, to cysteine residues of integral and peripheral membrane proteins and increases their affinity for membranes. Importantly, similar to phosphorylation, palmitoylation is reversible and is becoming recognised as instrumental for the regulation of protein function by modulating protein interactions, stability, folding, trafficking and signalling. Palmitoylation appears to play a central role in the biology of the Apicomplexa, regulating critical processes such as host cell invasion which is vital for parasite survival and dissemination. The recent identification of over 400 palmitoylated proteins in Plasmodium falciparum erythrocytic stages illustrates the broad spread and impact of this modification on parasite biology. The main enzymes responsible for protein palmitoylation are multi-membrane protein S-acyl transferases harbouring a catalytic Asp-HisHis-Cys (DHHC) motif. A global functional analysis of the repertoire of protein S-acyl transferases in Toxoplasma gondii and Plasmodium berghei has recently been performed. The essential nature of some of these enzymes illustrates the key roles played by this post-translational modification in the corresponding substrates implicated in fundamental processes such as parasite motility and organelle biogenesis. Toward a better understanding of the depalmitoylation event, a protein with palmitoyl protein thioesterase activity has been identified in T. gondii. TgPPT1/TgASH1 is the main target of specific acyl protein thioesterase inhibitors but is dispensable for parasite survival, suggesting the implication of other genes in depalmitoylation. Palmitoylation/depalmitoylation cycles are now emerging as potential novel regulatory networks and T. gondii represents a superb model organism in which to explore their significance.

show abstract

“…[9][10][11] The interaction of Ras with different membrane microdomains can affect its access to GEFs and effectors. 12 The membrane microdomains can promote distinct changes in Ras structure and orientation, which influence the preferred oligomerization states of Ras isoforms. Understanding the mechanisms of regulation of Ras signaling is the focus of research in many labs.…”

Section: Introductionmentioning

confidence: 99%