PXD043239-1

PXD043239 is an original dataset announced via ProteomeXchange.

Title	PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate
Description	The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2-phosphatase, PTEN. Despite huge investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signalling and constrained by pathway-feedback. In the absence of PTEN, the network is dramatically remodelled. A poorly understood, YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing, adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT-phosphorylation and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and SRC-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K-activation. hPLEKHS1-mRNA and activating-Y419-phosphorylation of hSRC correlated with PI3K-pathway activity in human prostate cancers. We propose that in PTEN-null cells, receptor-independent, SRC-dependent tyrosine-phosphorylation of PLEKHS1 creates positive-feedback that escapes homeostasis, drives PIP3-signalling and supports tumour progression.
HostingRepository	PRIDE
AnnounceDate	2023-08-23
AnnouncementXML	Submission_2023-08-23_10:33:09.099.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	DavidOxley
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Eclipse; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-06-23 06:27:27	ID requested
⏵ 1	2023-08-23 10:33:09	announced
2	2023-11-14 09:05:03	announced	2023-11-14: Updated project metadata.

Chessa TAM, Jung P, Anwar A, Suire S, Anderson KE, Barneda D, Kielkowska A, Sadiq BA, Lai IW, Felisbino S, Turnham DJ, Pearson HB, Phillips WA, Sasaki J, Sasaki T, Oxley D, Spensberger D, Segonds-Pichon A, Wilson M, Walker S, Okkenhaug H, Cosulich S, Hawkins PT, Stephens LR, PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate. Mol Cell, 83(16):2991-3009.e13(2023) [pubmed]

submitter keyword: IRS1, PTEN,PLEKHS1, prostate, PI3K

DavidOxley
contact affiliation	Babraham Institute, UK
contact email	david.oxley@babraham.ac.uk
lab head
DavidOxley
contact affiliation	Babraham Institute
contact email	david.oxley@babraham.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043239
     1. Label: PRIDE project
     2. Name: PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate