Cutting edge: Gab2 mediates an inhibitory phosphatidylinositol 3 '-kinase pathway in T cell antigen receptor signaling

Phosphatidylinositol 3'-kinase (PI3K) is a key component of multiple signal ing pathways, where it typically promotes survival, proliferation, and/or a dhesion. Here, we show that in TCR signaling, the scaffolding adapter Gab2 delivers an inhibitory signal via PI3K. Overexpression of Gab2 in T cell li nes inhibits TCR-evoked activation of the IL-2 promoter, blocking NF-AT- an d NF-kappa B-directed transcription. Inhibition is abrogated by mutating th e Gab2 p85-binding sites, by treatment with PI3K inhibitors or by cotransfe ction of phosphatase homolog of tensin, Our findings provide the first evid ence of a negative function for a scaffolding adapter in T cells and identi fy Gab2/PI3K-containing complexes as novel regulators of TCR signaling.