EEA1 LINKS PI(3)K FUNCTION TO RAB5 REGULATION OF ENDOSOME FUSION

GTPases and lipid kinases regulate membrane traffic along the endocyti c pathway by mechanisms that are not completely understood(1-4). Fusio n between early endosomes requires phosphatidyl-inositol-3-OH kinase ( PI(3)K) activity(5-7) as well as the small GTPase Rab5 (ref. 8). Exces s Rab5-GTP complex restores endosome fusion when PI(3)K is inhibited(5 ,9), Here we identify the early-endosomal autoantigen EEA1 (refs 10-12 ) which binds the PI(3)K product phosphatidylinositol-3-phosphate, as a new Rab5 effector that is required for endosome fusion. The associat ion of EEA1 with the endosomal membrane requires Rab5-GTP and PI(3)K a ctivity, and excess Rab5-GTP stabilizes the membrane association of EE A1 even when PI(3)K is inhibited. The identification of EEA1 as a dire ct Rab5 effector provides a molecular link between PI(3)K and Rab5, an d its restricted distribution to early endosomes(10) indicates that EE A1 may confer directionality to Rab5-dependent endocytic transport.