Allosteric inhibition rescues hydrocephalus caused by catalytically inactive Shp2

Abstract

SHP2, a protein tyrosine phosphatase (PTP) crucial in Ras-MAPK signaling, is associated with various human congenital diseases and cancers. Here, we show that the catalytically inactive Shp2C459S mutation results in communicating hydrocephalus, similar to the catalytically activating Shp2E76K and Mek1DD mutants. Unlike previous mutants, however, Shp2C459S/+ mutation uniquely affects ciliary development rather than neurogenesis, leading to reduced cilia density and impaired ciliary motility. Differential scanning fluorimetry revealed that SHP2C459S, SHP2E76K and SHP2C459S/E76K mutations all induce an open SHP2 conformation, but only SHP2C459S leads to aberrant GAB1 phosphorylation in cells expressing wild-type SHP2. This distinctive signaling pattern correlates with our observations in brain ventricular tissues of Shp2C459S/+ mice, where Erk and Stat3 activities remain normal but Gab1 phosphorylation is elevated. Critically, we show that the hydrocephalus phenotype in Shp2C459S mice can be mitigated by allosteric inhibition of Shp2. These findings suggest that Shp2-associated hydrocephalus is driven by conformational changes rather than altered catalytic activity. Our results underscore the therapeutic potential of conformation-specific allosteric inhibitors in targeting both catalytically active and inactive SHP2 mutants.