PXD048534

PXD048534 is an original dataset announced via ProteomeXchange.

Title	The ERK-dependent proteome is enriched in the mouse PDAC KPC RAS-dependent phosphoproteome
Description	Mutational activation of the KRAS oncogene is a major genetic driver of pancreatic ductal adenocarcinoma (PDAC) growth. KRAS-dependent PDAC growth is mediated primarily through persistent activation of the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade, one of the most extensively studied cancer signaling networks. While substrates of RAF and MEK kinases are highly restricted, ERK1/2 has been attributed to over 1,000 substrates. In this study, we used the highly selective ERK1/2 inhibitor, SCH772984, and proteomic and phosphoproteomic analyses to extend the repertoire of ERK-dependent phosphosites and phosphoproteins in PDAC. We validated the specificity of SCH772984 in our cell lines using multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). We then performed phosphoproteomics and global proteomics in a panel of PDAC cell lines and identified 5,117 ERK-dependent phosphosites on 2,252 proteins, of which 88% and 67%, respectively, were not previously associated with ERK. We then utilized our recently annotated serine/threonine kinome motif database to dissect the phosphoproteome and reveal an expansive ERK-regulated kinase network. We found that ERK- and immediate downstream kinase RSK-substrate motifs predominated after one hour of ERK inhibition, whereas cell cycle regulatory cyclin-dependent kinase motifs predominated by 24 h, reflecting a highly dynamic ERK-dependent phosphoproteome. We find compensatory activation of HIPK, CLK, PKN, PAK, and DYRK family kinases. Finally, using the genome-wide CRISPR-Cas9 dataset in the Cancer Dependency Map portal (DepMap), we determined that approximately 18% of ERK dependent phosphoproteins are essential for pancreatic cancer growth, and these are enriched in nuclear proteins. Together, our findings provide a system-wide profile of the mechanistic basis for ERK-driven pancreatic cancer growth.
HostingRepository	PRIDE
AnnounceDate	2024-05-29
AnnouncementXML	Submission_2024-05-29_09:06:47.709.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD048534
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Clint Stalnecker
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-14 10:27:14	ID requested
⏵ 1	2024-05-29 09:06:48	announced

10.6019/PXD048534;

10.1126/SCIENCE.ADK0850;

submitter keyword: KPC, RAS, PDAC,ERK, KRAS

Channing Der
contact affiliation	Lineberger Comprehensive Cancer Center at UNC Chapel Hill
contact email	channing_der@med.unc.edu
lab head
Clint Stalnecker
contact affiliation	UNC Chapel Hill
contact email	clints@email.unc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048534
     1. Label: PRIDE project
     2. Name: The ERK-dependent proteome is enriched in the mouse PDAC KPC RAS-dependent phosphoproteome