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PXD020805-1

PXD020805 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleA vascular phosphoproteome atlas unveils a functional Tie‑Wnt signalling axis in the liver
DescriptionSingle cell transcriptomic analyses (scRNAseq) of hepatocytes and liver endothelial cells (L-EC) have revolutionized the understanding of the spatial architecture of liver structure and function. The spatial alignment of L-EC and hepatocytes is pivotal for liver function in health and disease given that L-EC act as instructive gatekeeper of nearby hepatocytes including the maintenance of liver metabolic zonation in a Wnt-dependent manner. Advancing liver biology beyond the ’transcript-centric’ view of scRNAseq analyses is presently restricted by the limited resolution of proteomics and genome-wide techniques to analyse post-translational modifications. Here, by combining spatial cell sorting methodology with transcriptomic and quantitative proteomic/phospho-proteomic analyses, we established the first functionally and spatially-resolved proteome landscape of the liver endothelium, yielding deep mechanistic insight into zonated vascular signalling mechanisms. Phosphorylation of receptor tyrosine kinases (RTK) was detected preferentially in the central vein area resulting in an atypical enrichment of tyrosine phosphorylation. Prototypic biological validation of the identified strong phosphorylation gradient of the vascular RTK Tie1 by blockade resulted in the rapid peri-central dysregulation of the L-EC transcriptome. Notably, the expression of Wnt9b in L-EC was discovered as Tie receptor controlled with reciprocal regulation by FoxO1 and STAT3 transcription factors. Genetic inactivation of Tie1 in L-EC or antibody blockade resulted in reduced liver regeneration following partial hepatectomy with reduced Wnt ligand and Wnt target gene expression, including Axin2, Sox9, Tbx3 and Lgr5. Taken together, the study has yielded unparalleled insight into the spatial organization of L EC signalling and discovered a vascular Tie-Wnt signalling axis as regulator of liver function. The employed spatial sorting technique followed by phospho-proteomic analysis may be employed as a universally adaptable strategy for the spatial phosphoproteomic analysis of scRNAseq data-defined relevant cellular (sub)-populations.
HostingRepositoryPRIDE
AnnounceDate2021-05-21
AnnouncementXMLSubmission_2021-05-20_22:49:49.100.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterJingjing Shi
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListphosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-08-08 15:45:47ID requested
12021-05-20 22:49:49announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: phospho-proteome, liver, zonation, endothelial, vasculature, Tie, Wnt
Contact List
Hellmut G. Augustin
contact affiliationDivision of Vascular Oncology and Metastasis Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
contact emailh.augustin@dkfz.de
lab head
Jingjing Shi
contact affiliationGerman Cancer Research Center
contact emailjingjing.shi@dkfz.de
dataset submitter
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Dataset FTP location
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