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PXD025798

PXD025798 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitlePhosphoproteomic analysis of the Folliculin (FLCN) tumor suppressor reveals FLCN-dependent kinase signaling and TFEB regulation
DescriptionIn Birt-Hogg-Dubé (BHD) syndrome, germline mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address if FLCN is involved regulating cellular signaling pathways via protein and receptor phosphorylation we determined comprehensive complete phosphoproteomic profiles of FLCNPOS and FLCNNEG human renal tubular epithelial cells (RPTEC/TERT1). In total, 15744 phosphorylated peptides were identified, residing on 4329 phosphorylated proteins. Kinase activity inference analysis revealed that FLCN loss elevates phosphorylation of numerous kinases, including tyrosine kinases EPHA2 and MET, as well as activation of downstream MAPK1/3/6 and 8. Three non-canonical phosphorylation sites on EGFR (Tyr1125, Tyr1138 and Tyr1172) were higher phosphorylated upon FLCN loss together with enhanced phosphorylated EGFR substrates ABI, EPS8, ERRFL1, STAT1, PTK2 and CTNND1. In concordance, phosphosite specific signature analyses revealed an enrichment for EGFR signaling in FLCNNEG cells. Interestingly, we detected FLCN dependent phosphorylation of PIK3CD but no canonical downstream Akt/mTOR activation. In agreement with the induction of the E-box transcriptional gene expression signature upon FLCN loss, here we identified that phosphorylation of TFEB on Ser109, Ser114 and Ser122 is dependent on FLCN and absence of this phosphorylation results in constitutive nuclear localization of this transcription factor in FLCNNEG cells. Together, our study reveals enhanced phosphorylation of specific kinases and substrates in FLCNNEG renal epithelial cells, providing important insights in BHD-associated renal tumorigenesis and offering novel handles for the design of targeted therapies.
HostingRepositoryPRIDE
AnnounceDate2022-07-11
AnnouncementXMLSubmission_2022-07-11_05:57:29.069.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSander Piersma
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-05-05 01:53:33ID requested
12022-07-11 05:57:29announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Renal cell carcinoma, Folliculin, FLCN, signaling, phosphoproteomics, pTyr IP, INKA
Contact List
Connie Jimenez
contact affiliationAmsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, OncoProteomics Laboratory, Amsterdam, Netherlands
contact emailc.jimenez@amsterdamumc.nl
lab head
Sander Piersma
contact affiliationAmsterdam UMC
contact emails.piersma@amsterdamumc.nl
dataset submitter
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