# Proteome-Wide Analysis of Functional Phosphosites in the FGFR Family of Proteins: Insights from Large-Scale Phosphoproteomic Analysis

## TL;DR

This study identifies key phosphorylation sites in FGFR proteins linked to development and disease, offering insights for drug development.

## Contribution

A phosphoproteomic analysis revealing disease-associated phosphosites and co-modulated networks in FGFRs.

## Key findings

- Predominant phosphosites in FGFR1-4 were identified with differential abundance across conditions.
- 32 and 89 co-modulated phosphosites were found for FGFR3 and FGFR4, respectively.
- MAPK1 was identified as a potential upstream kinase of FGFR4.

## Abstract

Background: Fibroblast growth factor receptors (FGFRs) play a crucial role in tissue homeostasis and organ development by regulating cellular processes, including proliferation, differentiation, and survival. Dysregulation of FGFRs contributes to developmental disorders and carcinogenesis. As membrane-bound receptors, they represent promising targets for therapeutic intervention and drug development. Methods: This study employed a systematic in silico analysis of publicly available phosphoproteomics datasets to provide a comprehensive overview of the phosphorylation regulatory network of the FGFR family. Results: We identified predominant phosphosites in FGFR1-4 that exhibited differential abundance across diverse experimental conditions, specifically, Y653 in FGFR1; S453, Y586, Y656, and Y657 in FGFR2; S444 and S445 in FGFR3; and S573 in FGFR4. Our analysis identified 32 and 89 significantly co-modulated phosphosites on other proteins with FGFR3 and FGFR4, respectively. Beyond the upstream kinases from the FGFR family, we also identified MAPK1 as a potential upstream kinase of FGFR4. Furthermore, disease enrichment analysis revealed that proteins co-modulated with FGFR3 were primarily involved in skeletal developmental disorders, such as brachydactyly, short toe, and syndactyly of fingers, whereas those associated with FGFR4 were linked to various cancers. Conclusions: Our findings highlight key disease-associated phosphosites within the FGFRs and offer a foundation for advancing phosphosite-focused therapeutic research.