PXD021126-1

PXD021126 is an original dataset announced via ProteomeXchange.

Title	Structural analysis of the PTEN:P-Rex2 signaling node reveals how cancer-associated mutations coordinate to hyperactivate Rac1
Description	The PTEN:P-Rex2 complex is a commonly mutated signaling nodes in metastatic cancer. The dual-specificity phosphatase PTEN canonically functions as a tumour suppressor by hydrolysing PI(3,4,5)P3 to PI(4,5)P2 to inhibit PI3K-AKT signaling. P-Rex2 is a RhoGTPase guanine nucleotide exchange factor activated by both Gβγ and PI(3,4,5)P3 downstream of G protein-coupled receptor and receptor tyrosine kinase signaling. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cell proliferation. However, structural insights into both PTEN:P-Rex2 complex assembly and its dysregulation by cancer-associated mutations remain limited. Here, using crosslinking mass spectrometry and functional studies, we provide mechanistic insights into PTEN:P-Rex2 complex assembly and co-inhibition. PTEN is anchored to P-Rex2 by interactions between the PTEN C-terminal tail PDZ-interacting motif and the second PDZ domain of P-Rex2. This interaction bridges PTEN across the P-Rex2 surface, occluding PI(3,4,5)P3 hydrolysis. Conversely, PTEN both allosterically promotes an autoinhibited P-Rex2 conformation and occludes Gβγ binding. These insights allow us to define a new gain-of-function class of cancer mutations within the PTEN:P-Rex2 interface that uncouples PTEN inhibition of Rac1 signaling. In addition, we observe synergy between PTEN deactivating and P-Rex2 truncation mutations that combine to drive Rac1 activation to a greater extent than either single mutation alone.
HostingRepository	PRIDE
AnnounceDate	2022-08-12
AnnouncementXML	Submission_2022-08-12_06:13:39.784.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ralf Schittenhelm
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-26 00:13:12	ID requested
⏵ 1	2022-08-12 06:13:40	announced
2	2023-11-14 08:51:38	announced	2023-11-14: Updated project metadata.

10.1126/SCISIGNAL.ABC4078;

submitter keyword: PTEN, P-Rex2, cancer, metastasis, crosslinking mass spectrometry

Andrew M. Ellisdon
contact affiliation	Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia
contact email	andrew.ellisdon@monash.edu
lab head
Ralf Schittenhelm
contact affiliation	Monash University
contact email	ralf.schittenhelm@monash.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021126
     1. Label: PRIDE project
     2. Name: Structural analysis of the PTEN:P-Rex2 signaling node reveals how cancer-associated mutations coordinate to hyperactivate Rac1