MSCA Doctoral Network PhD position: MS-based proteomic profiling of unmodified and modified β-catenin- and β-catenin- peptide binder-sequences to decipher the role of protein PTMs in the IDR-mediated

Organisation/Company University of Milan Research Field Chemistry » Biochemistry Researcher Profile First Stage Researcher (R1) Positions PhD Positions Application Deadline 31 Oct 2026
- 23:59 (Europe/Vienna) Country Italy Type of Contract Temporary Job Status Full-time Hours Per Week 40 Offer Starting Date 1 Jan 2027 Is the job funded through the EU Research Framework Programme? Horizon Europe
- MSCA Marie Curie Grant Agreement Number Is the Job related to staff position within a Research Infrastructure? Yes

Offer Description

University of Milan
Project Title: MS-based proteomic profiling of unmodified and modified β-catenin
- and β-catenin-peptide binder-sequences to decipher the role of protein PTMs in the IDR-mediated β-catenin interactome

Objectives:

1. Develop and benchmark quantitative MS-based proteomic strategies to resolve PTM-dependent β-catenin interaction networks, integrating affinity-based interactomics with perturbation-driven proteomic readouts.

2. Define how individual and combinatorial PTMs—including S/T phosphorylation and R methylation—rewire β-catenin/IDR interaction networks and propagate into measurable cellular proteomic responses.

3. Establish quantitative proteomic signatures linking defined molecular perturbations of the β-catenin system to interaction-network remodeling and downstream pathway states, thereby distinguishing direct PTM-dependent interactions from secondary cellular responses.

Project Overview: Recent evidence shows that PRMT2 directly methylates β-catenin, promoting its proteasomal degradation and thereby attenuating downstream transcriptional activity. This places arginine methylation upstream in the regulation of β-catenin protein stability and provides a compelling mechanistic foundation for investigating β-catenin methylation and its crosstalk with phosphorylation. Building on these findings, this project will investigate how specific PTMs—and defined combinations of PTMs—encode different molecular and cellular states of the β-catenin regulatory network. Rather than considering PTMs exclusively as determinants of individual protein–protein interactions, the project will use β-catenin as a model system for developing a quantitative proteomics framework capable of connecting molecular PTM states, interaction-network remodeling, and cellular responses. Peptide-array pulldown assays and quantitative mass spectrometry-based proteomics will initially identify β-catenin interactions that are sensitive to phosphorylation, arginine methylation, or combinations of these modifications. Quantitative experimental designs will then determine the magnitude, specificity, and reproducibility of PTM-dependent interaction changes, allowing the construction of PTM-resolved interaction signatures rather than binary lists of interactors. The Maric lab (JMU, WP2) will provide expertise in peptide-array screening, assisting in the design and setup of the pulldown workflow and validation of β-catenin-binding IDR sequences. The Conibear lab (TUW, WP3) will synthesize defined S/T phosphorylated and R-methylated peptide variants and semi-synthetic β-catenin constructs, enabling systematic exploration of individual and combinatorial PTM states.
A central technological component of the project will be developed in the Bonaldi lab (UMI), where advanced quantitative proteomics will be used not simply to cat logue β-catenin-associated proteins, but to determine how experimentally controlled PTM states reshape interaction networks. MS-based workflows for comparative interactomics across multiple molecular states will be integrated with proteome-level responses to targeted perturbations of the corresponding regulatory machinery.
In particular, perturbation of selected kinases/phosphatases and PRMT-dependent pathways will provide an orthogonal cellular layer through which interaction-level observations can be tested. Comparing molecularly defined PTM states with cellular perturbation signatures will make it possible to identify coherent regulatory modules and prioritize PTM-dependent interactions that are functionally propagated through the β-catenin pathway. This strategy extends the concept of a PTM “barcode”: rather than defining a barcode solely as a combination of chemical modifications, PTM barcodes will be represented by multidimensional quantitative signatures comprising modification state, interaction-network configuration, and downstream proteomic response. Integration with structural studies (Madl, MUG) will provide a mechanistic interpretation of selected PTM-sensitive interactions, while integration with bioinformatic approaches (Pritišanac, HZM) will enable network-level analysis, prioritization of regulatory modules, and identification of proteomic signatures associated with specific β-catenin states. The resulting framework will reveal the molecular logic through which IDR-associated PTMs regulate β-catenin while