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

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.