Phosphatidylinositol 3 '-kinase blocks CD95 aggregation and caspase-8 cleavage at the death-inducing signaling complex by modulating lateral diffusion of CD95

Activation of phosphatidylinositol 3 ' -kinase (PI 3 ' -K) after ligation o f CD3 protects Th2 cells from CD95-mediated apoptosis. Here we show that pr otection is achieved by inhibition of the formation of CD95 aggregates and consequent activation of caspase-8. Inhibition of aggregate formation is me diated by changes in the actin cytoskeleton, which in turn inhibit lateral diffusion of CD95, reducing its diffusion coefficient, D, 10-fold. After cy tochalasin D treatment of stimulated cells, the lateral diffusion of CD95 i ncreases to the value measured on unstimulated cells, and CD95 molecules ag gregate to process caspase-8 and mediate apoptosis. Regulation of functiona l receptor formation by modulating lateral diffusion is a novel mechanism f or controlling receptor activity.