PXD036345

PXD036345 is an original dataset announced via ProteomeXchange.

Title	Cancer-associated Notch receptor variants lead to O-fucosylation defects that can deregulate Notch signaling
Description	NOTCH1 is a transmembrane receptor that initiates the Notch signaling pathway involved in embryonic development and maintenance of adult tissue homeostasis. The extracellular part of NOTCH1 is composed largely of EGF-like domains (EGFs) many of which can be O-fucosylated by protein O-fucosyltransferase 1 (POFUT1). O-fucosylation of NOTCH1 is necessary for its function. The Notch pathway is deregulated in many cancers, and alteration of POFUT1 has been reported in some cancers. Using the Biomuta and COSMIC databases, we selected 9 NOTCH1 variants that could cause a change in O-fucosylation of key EGFs. Cell-based N1 signaling assays, Notch ligand-binding assays and cell surface N1 analysis were used to determine the effect of each mutation on Notch activation. Then mass spectral glycoproteomic site mapping was used to identify alterations in the O-fucosylation of EGFs containing the selected mutation. One of the variants had few effects, two lead to a gain of function (GOF) and six to a loss of function (LOF). Most GOF and LOF could be associated with a change in O-fucosylation. Finally, by comparing our results with known NOTCH1 alterations in cancers from which our mutations originated, we were able to establish a correlation between our results and the known GOF or LOF of NOTCH1 in these cancers. This study shows that point mutations in NOTCH1 can lead to alterations in O-fucosylation that deregulate the Notch pathway and be associated with cancer processes.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_06:57:26.670.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	FLORIAN PENNARUBIA
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-26 08:02:07	ID requested
1	2022-10-21 06:52:17	announced
⏵ 2	2023-11-14 06:57:27	announced	2023-11-14: Updated project metadata.

Pennarubia F, Ito A, Takeuchi M, Haltiwanger RS, Cancer-associated Notch receptor variants lead to O-fucosylation defects that deregulate Notch signaling. J Biol Chem, 298(12):102616(2022) [pubmed]

submitter keyword: O-fucosylation, EGF repeat, Cancer,Notch, POFUT1

Robert S Haltiwanger
contact affiliation	Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
contact email	rhalti@uga.edu
lab head
FLORIAN PENNARUBIA
contact affiliation	Complex Carbohydrate Research Center (CCRC), University of Georgia
contact email	florian.pennarubia@uga.edu
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/2022/10/PXD036345

PRIDE project URI

• PRIDE
  1. PXD036345
     1. Label: PRIDE project
     2. Name: Cancer-associated Notch receptor variants lead to O-fucosylation defects that can deregulate Notch signaling