Essential role for Gab2 in the allergic response

Dos/Gab family scaffolding adapters (Dos, Gab1, Gab2) bind several signal r elay molecules, including the protein-tyrosine phosphatase Shp-2 and phosph atidylinositol-3-OH kinase (PI(3)K); they are also implicated in growth fac tor, cytokine and antigen receptor signal transduction(1). Mice lacking Gab 1 die during embryogenesis and show defective responses to several stimuli( 2,3). Here we report that Gab2(-/-) mice are viable and generally healthy; however, the response (for example, degranulation and cytokine gene express ion) of Gab2(-/-) mast cells to stimulation of the high affinity immunoglob ulin-epsilon (IgE) receptor Fc epsilon RI is defective. Accordingly, allerg ic reactions such as passive cutaneous and systemic anaphylaxis are markedl y impaired in Gab2(-/-) mice. Biochemical analyses reveal that signalling p athways dependent on PI(3)K, a critical component of Fc epsilon RI signalli ng, are defective in Gab2(-/-) mast cells. Our data identify Gab2 as the pr incipal activator of PI(3)K in response to FceRI activation, thereby provid ing genetic evidence that Dos/Gab family scaffolds regulate the PI(3)K path way in vivo. Gab2 and/or its associated signalling molecules may be new tar gets for developing drugs to treat allergy.