MAP kinase-activating death domain protein (MADD) regulates cell proliferation, survival and death through alternative mRNA splicing. Different isoforms have different effects: isoform 5 increases cell proliferation whereas isoform 2 decreases it; isoform 1 is susceptible to inducing apoptosis, isoform 5 is resistant []. MADD activates RAB3A, RAB3C and RAB3D by converting them from GDP-bound inactive forms to GTP-bound active forms []. MADD is a component of the TNFRSF1A signaling complex, linking the type 1 tumor necrosis factor receptor TNFRSF1A with MAP kinase activation []. MADD contains a tripartite DENN domain. In the nematode Caenorhabditis elegans, MADD is also known as regulator of presynaptic activity aex-3 [].
The Rab3 subfamily contains Rab3A, Rab3B, Rab3C, and Rab3D. All four isoforms were found in mouse brain and endocrine tissues, with varying levels of expression. Rab3A, Rab3B, and Rab3C localized to synaptic and secretory vesicles; Rab3D was expressed at high levels only in adipose tissue, exocrine glands, and the endocrine pituitary, where it is localized to cytoplasmic secretory granules []. Rab3 appears to control Ca2+-regulated exocytosis. The appropriate GDP/GTP exchange cycle of Rab3A is required for Ca2+-regulated exocytosis to occur, and interaction of the GTP-bound form of Rab3A with effector molecule(s) is widely believed to be essential for this process [].
