# Emergence of Catalytic Activity in VRK3: Phosphoproteomic Insights into the Regulatory Network of a Former Pseudokinase

## TL;DR

This paper explores how VRK3, once thought inactive, regulates cellular processes through phosphorylation and its potential role in diseases like cancer.

## Contribution

The study identifies high-confidence phosphorylation sites on VRK3 and links them to regulatory pathways and potential therapeutic targets.

## Key findings

- VRK3 has 32 high-confidence phosphorylation sites identified through phosphoproteomic data integration.
- Phosphorylation sites S59, S82, and S83 on VRK3 suggest functional significance.
- VRK3 phosphorylation is linked to ERK, Hippo, and GPCR pathways via upstream kinases and interactor proteins.

## Abstract

Vaccinia-Related Kinase 3 (VRK3) is increasingly recognized as a crucial signaling modulator in both normal and pathological processes. This kinase was long thought of as a catalytically inactive pseudokinase, until recently it was established to phosphorylate Barrier to Autointegration Factor (BAF) proteins through its extracatalytic domain. VRK3 regulates diverse cellular pathways through scaffold interactions and context-dependent phosphorylation. This review is centered around the phosphoregulatory network that modulates VRK3 phosphorylation with implications in its abundance and function. A large-scale phosphoproteomic data integration was performed by combining phosphoproteomics profiling and differential phosphorylation from 115 mass spectrometry studies, identifying 32 high-confidence phosphorylation sites on VRK3. Notably, VRK3 (S59), (S82), and (S83) were predominantly observed highlighting plausible functional significance. These phosphorylation sites share 33 potential upstream kinases, and multiple interactor proteins, which in combination are known to regulate ERK, Hippo, and GPCR pathways. These insights advance the understanding of phosphorylation control by kinases and highlight opportunities to target VRK3-associated networks for therapeutic intervention in diseases such as glioma and liver cancer.