PXD017006-2

PXD017006 is an original dataset announced via ProteomeXchange.

Title	TSC-Insensitive Rheb Mutations Induce Oncogenic Transformation Through a Combination of Hyperactive mTORC1 Signalling and Metabolic Reprogramming
Description	The mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1, that might act as driver oncogenes through aberrant hyperactivation of mTORC1. Here, we show that a number of recurrently occurring Rheb mutants drive hyperactive mTORC1 signalling through differing levels of insensitivity to the primary inactivator of Rheb, Tuberous Sclerosis Complex. We show that two activated mutants, Rheb-T23M and E40K, strongly drive increased cell growth and proliferation and anchorage-independent growth resulting in enhanced tumour growth in vivo. Proteomic analysis of cells expressing the mutations revealed, surprisingly, that these two mutants promote distinct oncogenic pathways with Rheb-T23M driving metabolic reprogramming and an increased reliance of glycolysis, while Rheb-E40K interacts with AMPK to regulate eukaryotic elongation factor 2 (eEF2) and autophagy. Our findings suggest that unique ‘bespoke’ combination therapies may be utilised to treat cancers according to which Rheb mutant they harbour.
HostingRepository	PRIDE
AnnounceDate	2021-04-22
AnnouncementXML	Submission_2021-04-21_23:19:52.564.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sean Humphrey
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2020-01-08 02:29:50	ID requested
1	2021-04-21 21:47:07	announced
⏵ 2	2021-04-21 23:19:53	announced	2021-04-22: Updated project metadata.
3	2024-10-22 05:21:26	announced	2024-10-22: Updated project metadata.

Xie J, De Poi SP, Humphrey SJ, Hein LK, Bruning JB, Pan W, Selth LA, Sargeant TJ, Proud CG, TSC-insensitive Rheb mutations induce oncogenic transformation through a combination of constitutively active mTORC1 signalling and proteome remodelling. Cell Mol Life Sci, 78(8):4035-4052(2021) [pubmed]

10.1007/S00018-021-03825-7;

curator keyword: Biomedical

submitter keyword: proteomes, Rheb,LC-MSMS, mTOR

Sean J Humphrey
contact affiliation	School of Life and Environmental Sciences & The Charles Perkins Centre, University of Sydney, Australia
contact email	sean.j.humphrey@gmail.com
lab head
Sean Humphrey
contact affiliation	The University of Sydney
contact email	sean.j.humphrey@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/04/PXD017006

PRIDE project URI

• PRIDE
  1. PXD017006
     1. Label: PRIDE project
     2. Name: TSC-Insensitive Rheb Mutations Induce Oncogenic Transformation Through a Combination of Hyperactive mTORC1 Signalling and Metabolic Reprogramming