Abstract:Dysregulation of the Ras oncogene in development causes developmental disorders, "Rasopathies," whereas mutational activation or amplification of Ras in differentiated tissues causes cancer. Rabex-5 (also called RabGEF1) inhibits Ras by promoting Ras mono-and di-ubiquitination. We report here that Rabex-5-mediated Ras ubiquitination requires Ras Tyrosine 4 (Y4), a site of known phosphorylation. Ras substitution mutants insensitive to Y4 phosphorylation did not undergo Rabex-5-mediated ubiquitination in cells a… Show more
“…As RIN1 is a RAS effector, this circuitry may constitute a negative feedback loop that limits RAS activation. Similarly, Rabex-5 mediated RAS ubiquitination requires tyrosine phosphorylation at the very Nterminus [73], suggesting that the activation of tyrosine kinases is part of this negative feedback loop.…”
Section: Posttranslational Modifications That Regulate Ras Interactiomentioning
RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.
“…As RIN1 is a RAS effector, this circuitry may constitute a negative feedback loop that limits RAS activation. Similarly, Rabex-5 mediated RAS ubiquitination requires tyrosine phosphorylation at the very Nterminus [73], suggesting that the activation of tyrosine kinases is part of this negative feedback loop.…”
Section: Posttranslational Modifications That Regulate Ras Interactiomentioning
RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.
“…Lysine deacetylases, HDAC6 and SIRT2, are suggested to negatively regulate K-RAS acetylation in cancer cells ( Yang et al, 2013 ; Knyphausen et al, 2016 ). RABEX5, an E3 Ubiquitin ligase, catalyzes mono- and di-ubiquitylation of H- and N-RAS, but not K-RAS, which downregulates RAS activity ( Xu et al, 2010 ; Yan et al, 2010 ; Washington et al, 2020 ). The ubiquitylation site(s) by RABEX5 remains unclear.…”
RAS is a founding member of the RAS superfamily of GTPases. These small 21 kDa proteins function as molecular switches to initialize signaling cascades involved in various cellular processes, including gene expression, cell growth, and differentiation. RAS is activated by GTP loading and deactivated upon GTP hydrolysis to GDP. Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) accelerate GTP loading and hydrolysis, respectively. These accessory proteins play a fundamental role in regulating activities of RAS superfamily small GTPase via a conserved guanine binding (G)-domain, which consists of five G motifs. The Switch regions lie within or proximal to the G2 and G3 motifs, and undergo dynamic conformational changes between the GDP-bound “OFF” state and GTP-bound “ON” state. They play an important role in the recognition of regulatory factors (GEFs and GAPs) and effectors. The G4 and G5 motifs are the focus of the present work and lie outside Switch regions. These motifs are responsible for the recognition of the guanine moiety in GTP and GDP, and contain residues that undergo post-translational modifications that underlie new mechanisms of RAS regulation. Post-translational modification within the G4 and G5 motifs activates RAS by populating the GTP-bound “ON” state, either through enhancement of intrinsic guanine nucleotide exchange or impairing GAP-mediated down-regulation. Here, we provide a comprehensive review of post-translational modifications in the RAS G4 and G5 motifs, and describe the role of these modifications in RAS activation as well as potential applications for cancer therapy.
“…Recently, Pfleger and colleagues 56 identified the phosphorylation at RAS Tyr4 as an indispensable factor required for the subsequent ubiquitination of RAS. Drosophila RAS, whose N-termini is identical to human H-, N- and K-RAS, was used to investigate the specific region of RAS that is related to RAS ubiquitination, suggesting a general effect of phosphorylation at Tyr4 across the RAS family.…”
Section: Phosphorylation: a Novel Promise For Anti-ras Therapeuticsmentioning
confidence: 99%
“…Although it has been widely acknowledged that JAK2, SRC, and EGFR are positive-regulators of RAS signaling, these kinases have also been discovered to promote RAS ubiquitination and inhibit its biological effects, thus implying a feedback regulatory mechanism to fine-tune RAS activity and ensure precise pathway output ( Fig. 1 ) 56 . Figure 1 Proposed model of RAS pTyr4 ubiquitination by Rabex-5.…”
Section: Phosphorylation: a Novel Promise For Anti-ras Therapeuticsmentioning
RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an ‘undruggable’ feature of RAS proteins. Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins. Therefore, the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties. A better understanding of RAS phosphorylation can contribute to future therapeutic strategies. In this review, we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways. Importantly, the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.
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