Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Decoding SOS: eIF2B as a Key Driver of Mutant KRAS Signaling and Tumorigenesis [Ribo-seq]

ABSTRACT: Beyond its established guanine exchange function (GEF) in regulating mRNA translation initiation, we demonstrate that eIF2B forms a unique complex with mutant, but not wild-type, KRAS and Son of Sevenless (SOS) in tumors, specifically when KRAS is in its active, GTP-bound state. Mechanistically, the catalytic eIF2Bε subunit binds to the allosteric RAS binding domain of SOS in complex with mutant KRAS, thereby enhancing KRAS GTP loading and activation. The eIF2Bε subunit, SOS and mutant KRAS complex localizes to the plasma membrane (PM), where it enhances the mutant KRAS activity and MAPK pathway signaling. In parallel, the translational function of eIF2B plays a key role in the upregulation of the glycosphingolipid (GSL) pathway, thereby promoting the localization and clustering of mutant KRAS at the PM. Genetic inactivation of eIF2Bε subunit significantly reduces the growth of mutant KRAS-driven tumors in both xenograft models and an autochthonous mouse model of lung adenocarcinoma. Notably, increased expression of the catalytic eIF2Bε subunit correlates with poor prognosis in human cancers harboring KRAS mutations. These findings reveal a previously unrecognized link between a core component of mRNA translation machinery and oncogenic KRAS function, offering new mechanistic insight and potential therapeutic avenues in mutant KRAS-driven malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304639 | GEO | 2026/08/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Decoding SOS: eIF2B as a Key Driver of Mutant KRAS Signaling and Tumorigenesis [RNA-seq]

Project description:Beyond its established guanine exchange function (GEF) in regulating mRNA translation initiation, we demonstrate that eIF2B forms a unique complex with mutant, but not wild-type, KRAS and Son of Sevenless (SOS) in tumors, specifically when KRAS is in its active, GTP-bound state. Mechanistically, the catalytic eIF2Bε subunit binds to the allosteric RAS binding domain of SOS in complex with mutant KRAS, thereby enhancing KRAS GTP loading and activation. The eIF2Bε subunit, SOS and mutant KRAS complex localizes to the plasma membrane (PM), where it enhances the mutant KRAS activity and MAPK pathway signaling. In parallel, the translational function of eIF2B plays a key role in the upregulation of the glycosphingolipid (GSL) pathway, thereby promoting the localization and clustering of mutant KRAS at the PM. Genetic inactivation of eIF2Bε subunit significantly reduces the growth of mutant KRAS-driven tumors in both xenograft models and an autochthonous mouse model of lung adenocarcinoma. Notably, increased expression of the catalytic eIF2Bε subunit correlates with poor prognosis in human cancers harboring KRAS mutations. These findings reveal a previously unrecognized link between a core component of mRNA translation machinery and oncogenic KRAS function, offering new mechanistic insight and potential therapeutic avenues in mutant KRAS-driven malignancies.

2026-08-01 | GSE304640 | GEO

Decoding SOS: eIF2B as a Key Driver of Mutant KRAS Signaling and Tumorigenesis [Ribo-seq]

Project description:Decoding SOS: eIF2B as a Key Driver of Mutant KRAS Signaling and Tumorigenesis [Ribo-seq]

| PRJNA1301971 | ENA

Decoding SOS: eIF2B as a Key Driver of Mutant KRAS Signaling and Tumorigenesis [RNA-seq]

Project description:Decoding SOS: eIF2B as a Key Driver of Mutant KRAS Signaling and Tumorigenesis [RNA-seq]

| PRJNA1301973 | ENA

Maintenance of p-eIF2 alpha levels by the eIF2B complex is vital for colorectal cancer

Project description:Protein synthesis is an essential cellular process highly deregulated in multiple tumour types, where control of several translation factors is hijacked to benefit oncogenic growth. Here we show that colorectal cancer (CRC) is characterized specifically by elevated levels of phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2alpha). In contrast to its canonical association with reduced translation rates, we reveal that CRC with high p-eIF2alpha has increased protein synthesis rates. Thus, we hypothesize that eIF2B, the sensor of p-eIF2 alpha, plays a central role in cells’ inability to relay this inhibitory signal. Using a combination of in cellulo biochemistry, phenotypic assays, and analysis of translation upon modulation of eIF2B subunits alpha and delta, the two eIF2B subunits responsible for sensing p-eIF2 alpha, we demonstrate that CRC cells require an intact eIF2B complex to sense p-eIF2 alpha. Crucially, we show that the alpha subunit of eIF2B is necessary to translate the oncogenic programs driven by APC loss, highlighting its central role in oncogenic transformation. To conclude, we demonstrate that whilst normal cells do not depend on eIF2B alpha, CRC cells require this eIF2B subunit for correct sensing of p-eIF2 alpha and regulation of their proteostasis, thus validating eIF2B alpha as a target for therapeutic intervention in CRC.

2025-01-09 | GSE249128 | GEO

Overexpression of KRAS-Q25A mutant with enhanced GTPase activity inhibits the progression of KRAS-G12D colorectal cancer

Project description:The high mutation rate of KRAS in cancers leads to consistent activation of downstream signaling and eventually promoting malignancy. While restoring GTP hydrolysis in KRAS-mutant tumors represents a promising therapeutic strategy, its mechanistic basis remains unclear. Our previous finding that mutation of the KRAS P4 pocket exhibited elevated intrinsic GTPase activity of KRAS, and therefore presented a promising new strategy to intervene KRAS mutated cancer. This exciting potential has now been verified in the current work. We explored how P4 mutants impact the progression of colorectal cancer, and found KRAS-Q25A, a P4 mutant with the most significant elevated GTPase activity, can inhibit the progression of CT26 cell, a commonly used colorectal cell line with KRAS-G12D mutation. Moreover, this inhibitory effect of KRAS-Q25A is depended on its GTP hydrolysis process. To assess the impact of KRAS-Q25A overexpression on the overall cellular state, we performed RNA sequencing on CT26 cells overexpressing either KRAS-WT or KRAS-Q25A.

2026-05-21 | GSE332549 | GEO

Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma [Mouse_hKPR.KPCHR_Sep25]

Project description:About 25% of cholangiocarcinoma (CCA) patients harbor KRAS mutations, being potentially amenable to direct KRAS inhibitors. Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms, in CCA preclinical models and patients. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and in immunocompetent allograft models. Consistently, we describe responses to the RAS(ON) multi-selective inhibitor daraxonrasib in two KRASG12X patients with advanced CCA. RAS-GTP inhibition also potentiates the activity of the current standard-of-care CCA therapy to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that both intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on reconstitution of RAS signalling. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signalling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.

2026-03-30 | GSE318390 | GEO

Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma [Mouse_iAKP_Abr24]

2026-03-30 | GSE318389 | GEO

Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma [Human_Abr24]

2026-03-30 | GSE318388 | GEO

BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition

Project description:KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proven challenging and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success due to activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1 thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.

2020-08-20 | GSE128385 | GEO

eIF2B-capturing viral protein NSs suppresses the integrated stress response

Project description:Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis revealed that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibited neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs is promising as a therapeutic ISR inhibitor.

2021-11-11 | GSE174764 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data