PXD043658-1

PXD043658 is an original dataset announced via ProteomeXchange.

Title	PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma
Description	Protein phosphatase 2A (PP2A) is a promiscuous enzyme that acts on many aspects of cellular physiology. It remains unclear however, which of the cellular processes are most perturbed upon inhibition of PP2A and how such perturbations could be exploited therapeutically. Here, we report an unanticipated sensitivity of the splicing machinery to phosphorylation changes in response to phosphatase 2A (PP2A) inhibition by LB-100 in colorectal adenocarcinoma. We observe enrichment for differentially phosphorylated sites within cancer-critical splicing nodes of U2 snRNP, SRSF and hnRNP proteins. These phosphorylation changes endow LB-100 treated colorectal adenocarcinoma cells with differential splicing patterns. Over 1000 exon skipping and intron retention events were enriched in PP2A-inhibited cells affecting the splicing of regulators of genomic integrity and DNA damage response. Finally, alternatively spliced transcripts downstream to LB-100 are predicted to be a source of neoantigens that can improve cancer treatment outcomes in response to immune checkpoint modulators. Collectively, our findings provide a potential explanation for the pre-clinical and clinical observations that inhibition of PP2A results in increased sensitivity of cancer cells to immune checkpoint blockade and DNA damaging agents.
HostingRepository	PRIDE
AnnounceDate	2024-06-16
AnnouncementXML	Submission_2024-06-16_02:08:28.915.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Onno Bleijerveld
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-10 13:47:50	ID requested
⏵ 1	2024-06-16 02:08:29	announced

10.1038/s44319-024-00128-3;

Dias MH, Liudkovska V, Montenegro Navarro J, Giebel L, Champagne J, Papagianni C, Bleijerveld OB, Velds A, Agami R, Bernards R, Cie, ś, la M, The phosphatase inhibitor LB-100 creates neoantigens in colon cancer cells through perturbation of mRNA splicing. EMBO Rep, 25(5):2220-2238(2024) [pubmed]

submitter keyword: PP2A inhibition, LB-100, phosphorylation, colon adenocarcinoma, alternative splicing

Onno B
contact affiliation	NKI Proteomics Facility, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
contact email	o.bleijerveld@nki.nl
lab head
Onno Bleijerveld
contact affiliation	The Netherlands Cancer Institute
contact email	o.bleijerveld@nki.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043658
     1. Label: PRIDE project
     2. Name: PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma