PXD043536

PXD043536 is an original dataset announced via ProteomeXchange.

Title	Proteomic mapping of the interactome of KRAS mutants identifies new features of RAS signalling networks and the mechanism of action of Sotorasib.
Description	RAS proteins are key regulators of cell signalling and are master regulators of different cell functions including cell proliferation, differentiation and cell death. Point mutations in the genes of this family are common, particularly in the KRAS. These mutations were thought to cause the constative activation of KRAS, but recent findings showed that some of these mutants can still cycle between active and inactive states. This observation together with the development of covalent KRASG12C inhibitors has led to the arrival to the clinic of KRAS inhibitors. However, most patients develop resistance to these targeted therapies, and we still lack effective treatments for other KRAS mutants. In order to accelerate the development of RAS targeting therapies we need to complete our characterisation of the molecular mechanisms that govern KRAS signalling networks and in particular determine if there are differences among the different KRAS mutants. Here we have used affinity purification mass-spectrometry proteomics to characterise the interactome of KRAS wild type and three KRAS mutants. Bioinformatic analysis associated with experimental validation allow us to map the signalling network mediated by the different KRAS proteins. Using this approach, we have also characterised the effect that clinically approved KRASG12 inhibitor sotorasib has in the interactome of these mutants and KRAS wild type. Our work indicates that this drug regulates the interactome and identifies new crosstalks between KRAS and its effector pathways including the AKT and JAK-STAT signalling modules.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:05:59.303.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kieran Wynne
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-04 08:21:20	ID requested
1	2023-10-15 12:04:15	announced
2	2023-11-14 09:05:58	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 06:06:02	announced	2024-10-22: Updated project metadata.

10.3390/cancers15164141;

Nolan A, Raso C, Kolch W, Kriegsheim AV, Wynne K, Matallanas D, Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib. Cancers (Basel), 15(16):(2023) [pubmed]

submitter keyword: APMS,RAS, Signalling

David Gomez
contact affiliation	Systems Biology Ireland University College Dublin.
contact email	david.gomez@ucd.ie
lab head
Kieran Wynne
contact affiliation	University College Dublin
contact email	kieran.wynne1@ucd.ie
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043536
     1. Label: PRIDE project
     2. Name: Proteomic mapping of the interactome of KRAS mutants identifies new features of RAS signalling networks and the mechanism of action of Sotorasib.