Posttranslational Modifications of RAS Proteins

Ahearn, Ian M.; Zhou, Mo; Philips, Mark R.

doi:10.1101/cshperspect.a031484

Cited by 67 publications

(65 citation statements)

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“…Post-translational modifications within the G-domain of RAS proteins present an additional layer of complexity in modulation of RAS activity and may provide novel avenues to target RAS-driven tumorigenesis ( Ahearn et al., 2018 , 2011 ). To date, PTMs such as ubiquitination, acetylation ,and methylation have been identified in G domain of RAS at multiple sites, including K104, K117, and K147 ( Ahearn et al., 2018 ). The modulatory effects of PTMs on RAS are dependent on the site and type ( Ahearn et al., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

KRAS Ubiquitination at Lysine 104 Retains Exchange Factor Regulation by Dynamically Modulating the Conformation of the Interface

et al. 2020

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Summary RAS proteins function as highly regulated molecular switches that control cellular growth. In addition to regulatory proteins, RAS undergoes a number of posttranslational modifications (PTMs) that regulate its activity. Lysine 104, a hot spot for multiple PTMs, is a highly conserved residue that forms key interactions that stabilize the RAS helix-2(H2)/helix-3(H3) interface. Mutation at 104 attenuates interaction with guanine nucleotide exchange factors (GEFs), whereas ubiquitination at lysine 104 retains GEF regulation. To elucidate how ubiquitination modulates RAS function, we generated monoubiquitinated KRAS at 104 using chemical biology approaches and conducted biochemical, NMR, and computational analyses. We find that ubiquitination promotes a new dynamic interaction network and alters RAS conformational dynamics to retain GEF function. These findings reveal a mechanism by which ubiquitination can regulate protein function.

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Section: Discussionmentioning

confidence: 99%

KRAS Ubiquitination at Lysine 104 Retains Exchange Factor Regulation by Dynamically Modulating the Conformation of the Interface

et al. 2020

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“…Palmitoylation of KRAS4A on cysteine 180 in the C-terminal membrane-targeting region is required for efficient plasma membrane association 1 . Because palmitoylation is reversible and short-lived 9 , palmitoylated RAS proteins continuously cycle between membrane compartments 10 . Whereas a C186S mutation of FLAG-KRAS4A, which blocks prenylation and therefore all membrane association, completely blocked associations with HK1 and HK2, a C180S mutation that blocks palmitoylation enhanced the associations ( Fig.…”

Section: Kras4a Binds To Hexokinasementioning

confidence: 99%

KRAS4A directly regulates hexokinase 1

Amendola¹,

Mahaffey²,

Parker³

et al. 2019

Nature

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The most frequently mutated oncogene in cancer is KRAS, which utilizes alternative fourth exons to generate two gene products, KRAS4A and KRAS4B, that differ only in their C-terminal membrane-targeting region 1. Because oncogenic mutations occur in exons 2 or 3, when KRAS is activated by mutation two constitutively active KRAS proteins are encoded, each capable of transforming cells 2. No functional distinctions among the splice variants have been established. Oncogenic KRAS alters tumor metabolism 3. Among these alterations is increased glucose uptake and glycolysis, even in the presence of abundant oxygen 4 (the Warburg Effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes 3-5 , direct regulation of metabolic enzymes has not been examined. We report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, establishing HK1 as an effector of KRAS4A. The interaction is unique to KRAS4A because the palmitoylation/depalmitoylation cycle of this RAS isoform permits co-localization with HK1 on the outer mitochondrial membrane (OMM). KRAS4A expression in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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“…lipidation is required for membrane association, sequence differences in the hypervariable region give rise to distinct and dynamic partitioning of the RAS isoforms between various endomembranes and the plasma membrane. This, in turn, contributes to isoform-specific localization and signaling (2).…”

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confidence: 99%

Regulation of large and small G proteins by ubiquitination

Dohlman

Campbell

2019

Journal of Biological Chemistry

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Edited by Mike Shipston Many sensory and chemical signal inputs are transmitted by intracellular GTP-binding (G) proteins. G proteins make up two major subfamilies: "large" G proteins comprising three subunits and "small" G proteins, such as the proto-oncogene product RAS, which contains a single subunit. Members of both subfamilies are regulated by post-translational modifications, including lipidation, proteolysis, and carboxyl methylation. Emerging studies have shown that these proteins are also modified by ubiquitination. Much of our current understanding of this posttranslational modification comes from investigations of the large G-protein ␣ subunit from yeast (Gpa1) and the three RAS isotypes in humans, NRAS, KRAS, and HRAS. G␣ undergoes both mono-and polyubiquitination, and these modifications have distinct consequences for determining the sites and mechanisms of its degradation. Genetic and biochemical reconstitution studies have revealed the enzymes and binding partners required for addition and removal of ubiquitin, as well as the delivery and destruction of both the mono-and polyubiquitinated forms of the G protein. Complementary studies of RAS have identified multiple ubiquitination sites, each having distinct consequences for binding to regulatory proteins, shuttling to and from the plasma membrane, and degradation. Here, we review what is currently known about these two well-studied examples, Gpa1 and the human RAS proteins, that have revealed additional mechanisms of signal regulation and dysregulation relevant to human physiology. We also compare and contrast the effects of G-protein ubiquitination with other post-translational modifications of these proteins. A variety of sensory and chemical signals are detected by receptors at the cell surface. In many cases, these inputs are transmitted by intracellular GTP-binding proteins (Fig. 1). Generally speaking, large G proteins are activated by seven transmembrane segment receptors, also known as G-proteincoupled receptors (GPCRs). 3 When these receptors bind to an agonist ligand, the G-protein ␣ subunit releases GDP, binds to GTP, and dissociates from the G␤␥ subunit dimer. GTP-bound G␣, G␤␥, or both go on to activate intracellular effectors that transduce the signal. Similarly, many small G proteins are activated by growth factor receptors and their associated guanine nucleotide-exchange factors (GEFs). As with GPCRs, GEFs promote the exchange of GTP for GDP and subsequent activation of downstream effectors. For both large and small G proteins, signaling persists until GTP is converted to GDP, and this inactivation step is accelerated by binding to GTPase-activating proteins (GAPs). Thus, GEFs and GAPs work in opposition to one another to regulate the activity of their cognate G proteins, both large and small. Here, we review newer mechanisms of G-protein regulation by ubiquitination, with a focus on a large G protein from yeast and three small G proteins from humans: NRAS, KRAS, and HRAS. We compare and contrast the effects of ubiquitination with ...

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Posttranslational Modifications of RAS Proteins

Cited by 67 publications

References 167 publications

KRAS Ubiquitination at Lysine 104 Retains Exchange Factor Regulation by Dynamically Modulating the Conformation of the Interface

KRAS Ubiquitination at Lysine 104 Retains Exchange Factor Regulation by Dynamically Modulating the Conformation of the Interface

KRAS4A directly regulates hexokinase 1

Regulation of large and small G proteins by ubiquitination

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