PXD060782

PXD060782 is an original dataset announced via ProteomeXchange.

Title	ARRDC3 tyrosine phosphorylation functions as a switch to control c-Src versus WWP2 interactions and distinct scaffolding functions
Description	Mammalian -arrestins are members of the same arrestin family as the ubiquitously expressed and extensively studied -arrestins. Arrestins share common structural elements including the conserved N- and C-arrestin-fold domains, polar core, finger loop, and C-terminal tail, all of which mediate protein-protein interactions. In -arrestins, these domains enable the control of G protein-coupled receptors (GPCR) signaling and scaffolding interactions with various signaling proteins including c-Src. By contrast, the repertoire of -arrestin scaffolding partners and regulatory mechanisms that control their interactions are not well understood. -arrestins differ considerably from -arrestins in the C-terminal region; -arrestins contain clathrin adaptor -adaptin binding sites whereas -arrestins harbor PPxY motifs, demonstrated to interact with WW domains of E3 ubiquitin ligases such as Itch and WWP2. Here we report the identification of a novel phosphorylation site, tyrosine (Y) 394, embedded in the C-terminal PPxY motif of -arrestin ARRDC3. The Y394 site functions as a phospho-regulatory switch to enable distinct ARRDC3 binding partners and scaffolding functions. We demonstrate that ARRDC3 Y394 phosphorylation promotes interaction with c-Src via its SH2 domain, whereas the non-phosphorylated form preferentially binds to WWP2. Our results further show that ARRDC3 Y394 phosphorylation and c-Src SH2 domain-dependent interaction enables regulation of c-Src activity, whereas ARRDC3 Y394 phosphorylation disrupts WWP2 interaction and perturbs ARRDC3-dependent lysosomal trafficking of the GPCR, protease-activated receptor-1. Together these findings indicate that ARRDC3 Y394 functions as a phospho-regulatory switch to enable selective binding to different partners that impact distinct scaffolding functions.
HostingRepository	PRIDE
AnnounceDate	2025-07-14
AnnouncementXML	Submission_2025-07-13_16:06:34.087.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Majid Ghassemian
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Bruker TDF format

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-13 11:06:06	ID requested
⏵ 1	2025-07-13 16:06:34	announced

10.1016/j.jbc.2025.110270;

Caplan M, Bardeleben C, Dhawan K, Plawat R, Kufareva I, Trejo J, ARRDC3 tyrosine phosphorylation functions as a switch to control c-Src versus WWP2 interactions and distinct scaffolding functions. J Biol Chem, 301(7):110270(2025) [pubmed]

submitter keyword: tyrosine phosphorylation, human,ARRDC3

JoAnn Trejo
contact affiliation	1Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093
contact email	jotrejo@health.ucsd.edu
lab head
Majid Ghassemian
contact affiliation	Scientist
contact email	mghassem@ucsd.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/2025/07/PXD060782

PRIDE project URI

• PRIDE
  1. PXD060782
     1. Label: PRIDE project
     2. Name: ARRDC3 tyrosine phosphorylation functions as a switch to control c-Src versus WWP2 interactions and distinct scaffolding functions