PXD020805-1

PXD020805 is an original dataset announced via ProteomeXchange.

Title	A vascular phosphoproteome atlas unveils a functional Tie‑Wnt signalling axis in the liver
Description	Single 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.
HostingRepository	PRIDE
AnnounceDate	2021-05-21
AnnouncementXML	Submission_2021-05-20_22:49:49.100.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jingjing Shi
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-08 15:45:47	ID requested
⏵ 1	2021-05-20 22:49:49	announced

Dataset with its publication pending

submitter keyword: phospho-proteome, liver, zonation, endothelial, vasculature, Tie, Wnt

Hellmut G. Augustin
contact affiliation	Division 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 email	h.augustin@dkfz.de
lab head
Jingjing Shi
contact affiliation	German Cancer Research Center
contact email	jingjing.shi@dkfz.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/05/PXD020805

PRIDE project URI

• PRIDE
  1. PXD020805
     1. Label: PRIDE project
     2. Name: A vascular phosphoproteome atlas unveils a functional Tie‑Wnt signalling axis in the liver