Allosteric inhibition rescues hydrocephalus caused by catalytically inactive Shp2

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 Shp2 ^C459S mutation results in communicating hydrocephalus, similar to the catalytically activating Shp2 ^E76K and Mek1 ^DD mutants. Unlike previous mutants, however, Shp2 ^C459S/+ mutation uniquely affects ciliary development rather than neurogenesis, leading to reduced cilia density and impaired ciliary motility. Differential scanning fluorimetry revealed that SHP2 ^C459S , SHP 2 ^E76K and SHP2 ^C459S/E76K mutations all induce an open SHP2 conformation, but only SHP2 ^C459S leads to aberrant GAB1 phosphorylation in cells expressing wild-type SHP2. This distinctive signaling pattern correlates with our observations in brain ventricular tissues of Shp2 ^C459S/+ mice, where Erk and Stat3 activities remain normal but Gab1 phosphorylation is elevated. Critically, we show that the hydrocephalus phenotype in Shp2 ^C459S 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.