PXD031662

PXD031662 is an original dataset announced via ProteomeXchange.

Title	Characterization of RAS and SLC3A2 signaling in multiple myeloma
Description	Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:50:36.581.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ryan Young
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF; Q Exactive; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-02-14 01:16:18	ID requested
1	2022-10-14 14:57:43	announced
⏵ 2	2023-11-14 07:50:38	announced	2023-11-14: Updated project metadata.

Yang Y, Bolomsky A, Oellerich T, Chen P, Ceribelli M, H, ä, upl B, Wright GW, Phelan JD, Huang DW, Lord JW, Van Winkle CK, Yu X, Wisniewski J, Wang JQ, Tosto FA, Beck E, Wilson K, McKnight C, Travers J, Klumpp-Thomas C, Smith GA, Pittaluga S, Maric I, Kazandjian D, Thomas CJ, Young RM, Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma. Nat Commun, 13(1):5469(2022) [pubmed]

submitter keyword: phosphoproteomes, NRAS,KRAS, SLC3A2, BioID2, multiple myeloma

Ryan Young
contact affiliation	National Cancer Institute National Institutes of Health Bethesda, MD United States
contact email	youngrm@mail.nih.gov
lab head
Ryan Young
contact affiliation	National Institutes of Health, National Cancer Institute
contact email	youngrm@nih.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031662
     1. Label: PRIDE project
     2. Name: Characterization of RAS and SLC3A2 signaling in multiple myeloma