Shp2 Regulates Vascular Endothelial Matrix Degradation in Phosphatase-Independent Manner

Shp2 is a protein tyrosine phosphatase that is implicated in many diseases such as developmental disorders and cancers. One of its suggested physiological functions is regulation of angiogenesis, which is often impacted in Shp2 pathologies. However, its role in angiogenesis is still poorly understood. In our work, we show that Shp2 plays a critical role in the initiation of the first step of angiogenesis: matrix degradation. Intriguingly, Shp2’s phosphatase activity and substrate binding are not needed for its regulation of this process. Our studies suggest that scaffolding by Shp2’s properly structured phosphatase domain mediates matrix degradation. This mechanism is supported by our analysis of Shp2 mutants causing Noonans Syndrome with Multiple Lentigines. These findings propose a novel mechanism by which Shp2 regulates angiogenic matrix degradation and presents Shp2’s phosphatase domain scaffolding as an attractive anti-angiogenic therapeutic target.