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A comprehensive and quantitative interactome of RAS

ABSTRACT: We investigated a comprehensive and quantitative interactome of RAS, a protein found to be a driver of many human cancers. This resource identifies interactors of the active form of RAS (nucleotide-dependent) as well as isoform-specific (KRAS, HRAS, and NRAS) interactors of RAS. Several of the proteins identified were confirmed as being important for cancer cell viability and senescence.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Sheng Zhang

LAB HEAD: Sheng Zhang

PROVIDER: PXD034847 | Pride | 2022-10-13

REPOSITORIES: Pride

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			Action	DRS
	Copy_of_M-S_List_of_Experimental_Samples-1.xlsx	Xlsx
	SethMiller10360343_HRasHeavyFlagLightNT.mgf	Mgf
	SethMiller10360343_HRasHeavyFlagLightNT.msf	Msf
	SethMiller10360343_HRasHeavyFlagLightNT.raw	Raw
	SethMiller10360343_HRasHeavyNTLightFlag.mgf	Mgf

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Publications

A Proteomic Approach Identifies Isoform-Specific and Nucleotide-Dependent RAS Interactions.

Miller Seth P SP Maio George G Zhang Xiaoyu X Badillo Soto Felix S FS Zhu Julia J Ramirez Stephen Z SZ Lin Hening H

Molecular & cellular proteomics : MCP 20220714 8

Active mutations in the RAS genes are found in ∼30% of human cancers. Although thought to have overlapping functions, RAS isoforms show preferential activation in human tumors, which prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific and nucleotide-dependent interactomes of the four RAS isoforms, KRAS4A, KRAS4B, HRAS, and NRAS. Many isoform-specific interacting proteins were identified, including HRAS-specific CARM1 and CHK1 and KRAS-specific PI ...[more]

PMID: 35839996

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Interrogation of the oncogenic RAS interactomes by BirA* based proximity labeling

Project description:We determined the specific protein interactomes of each RAS isoform (HRAS G12V, NRAS G12V and KRAS G12V) by BirA proximity-dependent biotin identification (BioID) in HEK-HT cells (folder hnk ras). We also determined protein interactomes of KRASG12V (folder: ras1) and HRASG12V (folder: ras2) in PIP5K1A deficient HEK-HT cells.

2018-07-08 | MSV000082583 | MassIVE

Transcriptional targets of oncogenic RAS proteins that mediate their ability to induce cellular transformation

Project description:Mutations in the NRAS oncogene are present in up to 20% of melanoma. Here, we show that interferon alpha-inducible protein 6 (IFI6) is necessary for NRASQ61K-induced transformation and melanoma growth. IFI6 was transcriptionally upregulated by NRASQ61K, and knockdown of IFI6 resulted in DNA replication stress due to dysregulated DNA replication via E2F2. This stress consequentially inhibited cellular transformation and melanoma growth via senescence or apoptosis induction depending on the RB and p53 pathway status of the cells. NRAS-mutant melanoma were significantly more resistant to the cytotoxic effects of DNA replication stress-inducing drugs, and knockdown of IFI6 increased sensitivity to these drugs. Pharmacological inhibition of IFI6 expression by the MEK inhibitor trametinib, when combined with DNA replication stress-inducing drugs, blocked NRAS-mutant melanoma growth. Collectively, we demonstrate that IFI6, via E2F2 regulates DNA replication and melanoma development and growth, and this pathway can be pharmacologically targeted to inhibit NRAS-mutant melanoma. MEL-ST cells expressing either empty vector or mutant oncogenic RAS genes (HRAS v12, KRAS v12, NRAS Q61K) were used to isolate total RNA. The RNA was then used to perform gene expression analyses using the Illumina HumanHT-12 V4.0 Expression BeadChip array.

2016-09-08 | E-GEOD-62827 | biostudies-arrayexpress

Oncogenic potential of RAS isoforms in melanocytes

Project description:We compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. While both NRAS and KRAS activate MAPK signaling, only NRAS enhances MYC activity in these cells. Our data suggests that the activity of specific RAS isoforms is context dependent and provides a possible explanation for the prevalence of NRAS mutations in melanoma.In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways. Keywords: RAS isoforms Common Reference

2010-06-10 | E-GEOD-6194 | biostudies-arrayexpress

Oncogenic potential of RAS isoforms in melanocytes

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Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma

Project description:Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient-derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

2024-03-15 | PXD047878 | Pride

BioID proximity biotinylation-MS analysis of human main RAS GTPases in K-562 CML cells

Project description:The human main RAS GTPases (KRAS4A, KRAS4B, NRAS and HRAS) represent major hubs of cellular signal transduction and are highly mutated in various different cancer entities. RAS GTPases are tightly controlled via different molecular mechanisms in order to coordinate their cellular signaling activity integrating extracellular and intracellular signals. In order to identify novel regulators of RAS signaling activity we have devised a BioID (BirA*-based proximity biotinylation)-Mass spectrometry-based approach in the human K-562 CML cell line. The deposited data set contains the acquired MS data after inducible expression, biotinylation, purification and proteomic analysis of KRAS4A, KRAS4B, NRAS and HRAS proteins. Further detailed information can be found in the appended sample data sheet and in the material and methods section of the manuscript Bigenzahn et al..

2018-12-03 | PXD011280 | Pride

Integrated Phosphoproteomics and Transcriptional Classifiers Reveal Hidden RAS Signaling Dynamics in Multiple Myeloma

Project description:A major driver of multiple myeloma is thought to be aberrant signaling, yet no kinase inhibitors have proven successful in the clinic. Here, we employ an integrated, systems approach combining phosphoproteomic and transcriptome analysis to dissect cellular signaling in multiple myeloma to inform precision medicine strategies. Collectively, these predictive models identify vulnerable signaling signatures and highlight surprising differences in functional signaling patterns between NRAS and KRAS mutants invisible to the genomic landscape. Transcriptional analysis suggests that aberrant MAPK pathway activation is only present in a fraction of RAS-mutated vs. WT RAS patients. These high-MAPK patients, enriched for NRAS Q61 mutations, have inferior outcomes whereas RAS mutations overall carry no survival impact. We further develop an interactive software tool to relate pharmacologic and genetic kinase dependencies in myeloma. These results may lead to improved stratification of MM patients in clinical trials while also revealing unexplored modes of Ras biology.

2019-03-06 | PXD011551 | Pride

Transcription profiling of human peripheral blood mononuclear cells WITH a germline NRAS mutation vs controls reveals NRAScauses a novel human autoimmune lymphoproliferative syndrome (ALPS)

Project description:The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4-, CD8- ab T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving tumor necrosis factor receptor (TNFR) superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling which markedly decreases the pro-apoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyl-transferase inhibitors (FTIs) should be examined in human autoimmune and lymphocyte homeostasis disorders. Experiment Overall Design: Describes the discovery of a new gene underlying a novel type of autoimmune lymphoproliferative syndrome, and characterizes the mechanisms involved in the pathogenesis of the disease.

2008-04-04 | E-GEOD-7345 | biostudies-arrayexpress

Germline NRAS mutation causes a novel human autoimmune lymphoproliferative syndrome

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Gene expression data of Kas-/- mouse emobryonic fibroblasts transfected with KRAS siRNAs

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