PXD066179

PXD066179 is an original dataset announced via ProteomeXchange.

Title	ERK inhibits Cic repressor function via multisite phosphorylation
Description	The receptor tyrosine kinase (RTK)/Extracellular Signal-Regulated Kinase (ERK) signaling pathway controls cell proliferation, differentiation, and survival. How ERK activation is relayed to its phosphorylation targets is not well understood. The transcriptional repressor Capicua (Cic) has emerged as a key target for ERK-mediated downregulation in Drosophila and mammals, and mutations in human CIC result in cancer and neurological diseases. Phosphorylation by ERK is critical for Cic downregulation, but the identities of phosphosites in Drosophila Cic are unknown. Here, we identify sites of phosphorylation in Cic that are directly targeted by ERK and validate their developmental functions in vivo using mutant Cic variants. Cic phosphosites are distributed throughout the length of the protein, and a group of centrally located sites appears to have a primary role in Cic downregulation. Cic mutated in 20 high-confidence sites behaves as a “super-repressor” in vivo that is largely insensitive to ERK-mediated downregulation, despite fully retaining the ability to bind to ERK. No single site is sufficient to turn off Cic activity; instead, we find that ERK must phosphorylate multiple sites in Cic simultaneously to achieve full downregulation. This multisite phosphorylation likely targets phosphodegrons that are recognized by ubiquitin ligases such as Ago/FBXW7 and contributes to Cic degradation. This study advances our understanding of the molecular mechanisms of signal interpretation downstream of the RTK/ERK signaling network.
HostingRepository	PRIDE
AnnounceDate	2026-03-16
AnnouncementXML	Submission_2026-03-16_08:30:12.525.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alexey Veraksa
SpeciesList	scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: NEWT:7227;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-15 12:04:33	ID requested
⏵ 1	2026-03-16 08:30:13	announced

10.1242/jcs.264327;

Paul S, Ilkhani K, Strozewski N, Yang L, Denberg DW, Christalin W, Locke V, Shvartsman SY, Veraksa A, ERK inhibits Capicua repressor function via multisite phosphorylation. J Cell Sci, 139(6):(2026) [pubmed]

submitter keyword: ERK, multisite phosphorylation,Capicua, Drosophila

Alexey Veraksa
contact affiliation	Biology Department, University of Massachusetts Boston, Boston, MA, USA
contact email	alexey.veraksa@umb.edu
lab head
Alexey Veraksa
contact affiliation	University of Massachusetts Boston
contact email	alexey.veraksa@umb.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/2026/03/PXD066179

PRIDE project URI

• PRIDE
  1. PXD066179
     1. Label: PRIDE project
     2. Name: ERK inhibits Cic repressor function via multisite phosphorylation