Endocytosis is a multifaceted regulator of cell surface-to-nucleus communication. It can dampen signaling by sending receptors to lysosomes for degradation. However, recent studies suggest that some receptors continue to signal from within endosomes. Now, Marta Miaczynska, Marino Zerial (Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany), and colleagues show that endosomes themselves are needed to transduce certain proliferation signals to the nucleus.
Endosome trafficking relies on a small GTPase called Rab5. Activation of Rab5 by binding of extracellular factors such as EGF to their receptors stimulates endocytosis. Zerial's group shows that some EGF-containing endosomes trigger nuclear responses via two newly identified Rab effectors, APPL1 and APPL2. Thus, EGF can elicit signal transduction cascades from both endosomes and the plasma membrane.
The APPL proteins were found in a unique subset of Rab5- and EGF-containing endosomes. GTP hydrolysis by Rab5 then released APPLs from the membranes so that they could enter the nucleus. There, APPLs interacted with a histone deacetylase and chromatin-remodeling proteins that are needed for cell cycle progression—and thus EGF's proliferative effects. Loss of APPL or its interaction with Rab5 blocked DNA synthesis and cell proliferation.
Besides EGF, oxidative stress also relocated APPLs to the nucleus, and the authors believe that other growth factors will have the same effect. Miaczynska is now interested in determining whether the APPL-containing membranes are simply transport vesicles, subcompartments of early endosomes, or bona fide organelles. “If an organelle linked to endocytosis exists that is dedicated to signaling, it would increase the possibilities of regulation in the cell,” says Zerial. “It would explain why different cells respond so differently to growth factors, because the amount of this pathway differs. In essence, the ability of a cell to respond to growth factors depends not only on the set of receptors and signaling molecules but also on their trafficking pathways.” ▪