Active G _αi2 sequesters RASA2 to promote RAS activation and T cell hyperresponsiveness. (A) In normal T cells, TCR stimulation leads to RAS activation (1), which drives T cell activation and proliferation (2). RASA2, a GAP for RAS, facilitates the hydrolysis of RAS-GTP into inactive RAS-GDP (3). In this way, RASA2 functions to inactivate RAS and limit normal T cell responses. (B) Activating mutations in G_αi2 sequester RASA2 away from RAS in the Golgi apparatus (1). Since RASA2 normally accelerates the hydrolysis of RAS-GTP into the inactive RAS-GDP, this sequestration promotes TCR-induced activation of RAS (2) and downstream signaling required for T cell growth and proliferation. Consequently, in patients with activating mutations in G_αi2, the stimulatory requirement for full T cell activation and proliferation is reduced by increased RAS activation. The enhanced TCR-induced activation and proliferation (3) may explain the autoimmunity (4) observed in some patients.