# SHP2 regulates VEGFR2 Y1175/PLCγ signaling to impair tumor endothelial barrier stability

## TL;DR

This study shows how SHP2 and PLCγ work together in blood vessels to cause leaks in tumors, and targeting them could help treat cancer.

## Contribution

Identifies SHP2 as a key partner of PLCγ in VEGFR2 signaling, offering new therapeutic targets for vascular normalization in cancer.

## Key findings

- SHP2 binds to VEGFR2 pY1175 and collaborates with PLCγ to increase vascular permeability.
- Blocking the VEGFR2/PLCγ/SHP2 pathway reduces endothelial leakage in tumor and healthy vessels.
- High PLCγ or SHP2 expression in kidney cancer vessels correlates with increased vascular leakage.

## Abstract

Tumor vasculature is abnormally formed, with an endothelial cell (EC) barrier lacking integrity, resulting in hyperpermeable vessels. Elevated VEGFA levels drive the formation of the dysfunctional vasculature by activating VEGFR2 signaling. The VEGFR2 tyrosine site pY1175 was recently shown to stimulate a PLCγ/eNOS/Src pathway, promoting vascular leakage and hindering therapeutic targeting and anti-tumor immunity. High endothelial PLCγ levels correlated to poor kidney cancer prognosis, which indicated endothelial PLCγ as a prognostic biomarker. In this study, we reveal SHP2 as a binding partner of pY1175 and show that SHP2 cooperates with PLCγ to mediate VEGFA-induced permeability in both healthy and tumor vasculatures. Targeting the VEGFR2/PLCγ/SHP2 axis—genetically or pharmacologically—reduces EC junctional phosphorylation to prevent VE-cadherin internalization, followed by reduced macromolecular leakage. Tumor EC expression of PLCγ or SHP2 is associated with vascular leakage in human kidney cancer, underscoring their potential as targets for vascular normalization and biomarkers for disease progression and treatment response.

•The phosphatase SHP2 forms a complex with PLCγ at VEGFR2 pY1175 in endothelial cells•VEGFR2/PLCγ/SHP2 signaling activates eNOS/Src, causing VEC disruption and leakage•Targeting the pathway stabilizes the barrier in both healthy and tumor vasculatures•PLCγ or SHP2 expression in human RCC vessels correlates with enhanced leakage

The phosphatase SHP2 forms a complex with PLCγ at VEGFR2 pY1175 in endothelial cells

VEGFR2/PLCγ/SHP2 signaling activates eNOS/Src, causing VEC disruption and leakage

Targeting the pathway stabilizes the barrier in both healthy and tumor vasculatures

PLCγ or SHP2 expression in human RCC vessels correlates with enhanced leakage

Microenvironment; molecular biology; cell biology; cancer