VALERIA CAVALLI & JEAN GRUENBERG

Although we have learned a great deal in recent years about the molecular machinery involved in membrane traffic, we still know relatively little about the regulation of these processes by extracellular signals. It is well established that, in many instances, ligand binding to a receptor triggers the internalization of the receptor–ligand complex and its transport through the endocytic pathway towards lysosomal degradation, recycling to the cell surface or other locations in the cell. By contrast, the bulk of endocytosis is often viewed as a constitutive process that ensures the continuous recycling of membrane components. In a recent paper (Mol. Cell 7, 421–432; 2001), Cavalli and co-workers now show that a well-characterized signalling pathway that involves the MAP kinase family member p38 can regulate the rate of endocytosis by modulating the activity of the guanyl-nucleotide dissociation inhibitor RabGDI.

Rab proteins are involved in a multitude of membrane traffic and fusion events, including the endocytic pathway. They cycle between active (GTP-bound) and inactive (GDP-bound), as well as between membrane-bound and cytosolic states. The latter cycle is regulated by RabGDI, which extracts GDP-bound Rab proteins from the membrane, allowing their recycling to and subsequent activation at the next membrane. Both cycles are thought to ensure the directionality of membrane traffic.

Cavalli et al. searched for an upstream regulator of RabGDI that would increase its capacity to extract Rab5—a Rab protein involved in early steps of endocytic transport—from endosomal membranes. The activity they identified was stress-activated p38 kinase, which directly phosphorylates serine 121 of RabGDI. In intact cells, the p38 pathway can be activated by various cellular stresses, such as oxidative stress or UV irratiation. Under stress situations, Rab5 and its effector EEA1 were released from endosomes, and this depends on the presence of serine 121 in RabGDI. The image shows that the association of EEA1 (red) with endosomes is resistant to H2O2-induced release in the presence of the RabGDI S121A mutant (co-transfected with a GFP construct (green) to label transfected cells). Most importantly, exposure of cells to UV light or H2O2 increased the rate of endocytosis in normal cells but not in cells lacking p38. Furthermore, basal levels of p38 activity seem to be required for the basal rate of endocytosis. Taken together, these data point to the existence of a pathway that links p38 and RabGDI to both constitutive endocytic membrane transport and its regulation in response to external stress stimuli.

But why increase the rate of endocytosis in times of stress? Cavalli et al. speculate that the increase in endocytosis in response to extracellular stresses might allow more efficient internalization of cell surface components for repair, storage or degradation. Although this intriguing hypothesis requires further support, this study provides a provocative start in identifiying the molecular mechanisms through which fundamental membrane trafficking pathways can be regulated by environmental stimuli. It is likely that more links between extracellular signals and the basic membrane traffic machinery will be unveiled in the future.