Dataset Information

Protein-Protein Interactions Maps of the KRAS Pathway in HEK293 and A549 cells

ABSTRACT: Activating mutations in RAS GTPases drive one fifth of cancers, but poor understandings of many RAS effectors and regulators, and of the roles of their different paralogs, continue to impede drug development. We developed a multi-stage discovery and screening process to understand RAS function and identify RAS-related susceptibilities in lung adenocarcinoma. Using affinity purification mass spectrometry (AP/MS), we generated a protein-protein interaction map of the RAS pathway containing thousands of interactions. From this network we constructed a CRISPR dual knockout library targeting 119 RAS-related genes that we screened for genetic interactions (GIs). We found important new effectors of RAS-driven cellular functions, RADIL and the GEF RIN1, and over 250 synthetic lethal GIs, including a potent KRAS-dependent interaction between RAP1GDS1 and RHOA. Many GIs link specific paralogs within and between gene families. These findings illustrate the power of the multiomic approach to identify synthetic lethal combinations for hitherto undruggable cancers.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Embryo, Lung, Epithelial Cell, Kidney

DISEASE(S): Carcinoma

SUBMITTER: Janos Demeter

LAB HEAD: Peter Kent Jackson

PROVIDER: PXD015485 | Pride | 2021-07-24

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	140919_NMooney_Jackson_Rap1B_GDP_1.raw	Raw
	140919_NMooney_Jackson_Rap1B_GDP_1.raw_20190722_Byonic(1).pride.mgf.gz	Mgf
	140919_NMooney_Jackson_Rap1B_GDP_1.raw_20190722_Byonic(1).pride.mztab.gz	Mztab
	140919_NMooney_Jackson_Rap1B_GDP_1.raw_20190722_Byonic1.mgf	Mgf
	140919_NMooney_Jackson_Rap1B_GDP_1.raw_20190722_Byonic1.mzid.gz	Mzid

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Publications

Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities.

Kelly Marcus R MR Kostyrko Kaja K Han Kyuho K Mooney Nancie A NA Jeng Edwin E EE Spees Kaitlyn K Dinh Phuong T PT Abbott Keene L KL Gwinn Dana M DM Sweet-Cordero E Alejandro EA Bassik Michael C MC Jackson Peter K PK

Cancer discovery 20200729 12

Activating mutations in RAS GTPases drive many cancers, but limited understanding of less-studied RAS interactors, and of the specific roles of different RAS interactor paralogs, continues to limit target discovery. We developed a multistage discovery and screening process to systematically identify genes conferring RAS-related susceptibilities in lung adenocarcinoma. Using affinity purification mass spectrometry, we generated a protein-protein interaction map of RAS interactors and pathway comp ...[more]

PMID: 32727735

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