Rabex-5, also called RabGEF1 and RAP1, was identified as a guanine nucleotide exchange factor (GEF) for Rab5, a member of the Ras superfamily of small Rab GTPases. Rabex-5 generates the GTP-bound active form of Rab5 and forms a tight association with its effector protein Rabaptin-5. This complex localizes to endosomal membranes where it functions as a key regulator of vesicular trafficking during early endocytosis. Rabex-5 is also monoubiquitinated and has ubiquitin ligase activity that regulates its recruitment to early endosomes. The conformational change between Rab5 GTP/GDP states is essential for its biological function as a rate limiting regulator at multiple steps during endocytosis. Through its control of endosomal trafficking and endocytosis, Rabex-5 has been shown to negatively regulate NGF-mediated neurite outgrowth as well as FcεRI-dependent mast cell activation. |