# The R451 site is critical for PTPN18 to exert tumor suppressive effects in breast cancer through the negative regulatory interacting protein fibrillarin

## TL;DR

This study shows that the R451 site of PTPN18 is crucial for its tumor-suppressing role in breast cancer by interacting with fibrillarin.

## Contribution

The study identifies a novel interaction between PTPN18 and fibrillarin, revealing a new tumor suppression mechanism in breast cancer.

## Key findings

- PTPN18 interacts with fibrillarin via R451 and V187 sites, promoting fibrillarin degradation.
- PTPN18 negatively regulates fibrillarin to affect RNA synthesis and signaling pathways.
- PTPN18-fibrillarin interaction inhibits breast cancer cell proliferation and tumor growth.

## Abstract

PTPN18 is a member of the PEST (proline-glutamic acid-serine-threonine rich sequence) protein tyrosine phosphatase subfamily that has been intensively studied in immune cells. Here, we identified a novel PTPN18-interacting protein, fibrillarin (FBL), through mass spectrometry analysis and clarified the binding sites and interaction motifs via peptide mapping. The R451 site of PTPN18 and the V187 site of FBL dominate the interaction between PTPN18 and FBL. Further studies suggest that PTPN18, but not PTPN18 R451A, can dephosphorylate the Y313 site of FBL and can reduce the protein expression level of FBL by promoting its ubiquitin proteasome degradation. In addition, PTPN18 can affect its downstream functions, including the MAPK signaling pathway and methylation of rRNA 2′-O and histone H2AQ104 sites, as well as RNA synthesis through negative regulation of FBL, whereas PTPN18 R451A cannot. As a result, the interaction between PTPN18 and FBL affects the proliferation and apoptosis of breast cancer cells, thus inhibiting tumor growth. This study reveals a novel mechanism through which PTPN18 inhibits breast cancer progression and further refines the PTPN18 protein interaction network, which is important for understanding its role in cell signaling, revealing disease mechanisms, discovering new drug targets, and developing new treatments.