Endocytosis is the process used by eukaryotic cells to internalize molecules and particulate matter into vesicles. Endocytic uptake of nutrients, antigens, signaling receptors, viruses and microorganisms is accomplished by a number of distinct mechanisms. Importantly, endocytosis and signal transduction are intimately connected.

For long time endocytosis has been considered just instrumental to terminate signaling by internalization and degradation of activated receptor complexes but in the past ten years the fundamental role of endosomes and thus of endocytosis in signaling has emerged. Indeed, elegant work from many research groups has shown that, beside the acquisition of nutrient and cell desensitization, endocytosis also propagates signals (1-4). Indeed, the endocytic pathway is able to activate signal transduction routes, with endosomes being signaling platform important for spatio-temporal resolution of signals (1-4).

Now, a series of recent evidences point out to a new major role of endocytosis (5-7). Indeed, it has been discovered that endocytosis takes part in remodeling of the apical surface during epithelial morphogenesis (5-7). Morphogenesis requires remodeling of cell shape and the role of the cytoskeleton in the regulation of plasma membrane’s dynamics and structure has been known since a long time. However, remodeling requires: i) flattening of the apical surface to induce tissue invagination, and ii) stretching of the apical surface to accomplish tissue elongation. High levels of membranes turnover, suggesting involvement of membrane traffic, accompany these changes at the apical membrane. Using Drosophila embryos, it was established that flattening of apical membrane was driven by endocytosis (7). Indeed, a massive increase in apical endocytosis, via formation of tubular invaginations from which Rab5-positive endosomes were generated, accompanied the apical membrane morphological changes. This pathway was proven to be dependent on dynamin and on the Rab5 effector Rabankyrin (7). Thus, flattening of the apical surface was associated with biogenesis of endosomes and endocytosis dynamics. Interestingly, in this process dynamin doesn’t seem to be important for its role on membrane fission. Indeed, in shibire (a temperature sensitive allele of dynamin) mutant of Drosophila tubular endocytosis during morphogenesis was completely abolished and apical flattening did not take place (7). As dynamin also regulates actin reorganization (8-9), it was suggested that actin cytoskeleton and tubular endocytosis are coordinated by dynamin (7). The participation in this process of Rabankyrin, a protein involved in macropinocitosis, again suggests a coordinate regulation of membrane and actin cytoskeleton (7).

These extremely interesting data raise a number of questions:

1. What is the role of Rab5 in this process? Does it directly trigger the formation of tubules from the plasma membrane or is it recruited later on tubules to control their processing and the formation of endosomes through Rabankyrin-5? Are other Rabs involved?
2. Tubular endocytosis is usually called CLIC (clathrin-independent carrier) pathway. However, CLIC pathway appears to be different from the one required for morphogenesis as blocking of dynamin in CLIC results in the elongation of tubular intermediates. Consequently, are there several tubular endocytosis pathways?
3. What happens to the internalized membranes? Do they contribute to lateral growth of plasma membrane or are they degraded or stored in lysosomes?
4. Is this mechanism universal? Is it present in other organisms and in particular in vertebrates?

These question and many others will hopefully be addressed in the next future.

References

1. Miaczynska, M., Pelkmans, L. & Zerial, M. Not just a sink: endosomes in control of signal transduction. Curr. Opin. Cell Biol. 16:400-406 (2004).
2. Scita, G. & Di Fiore, P.P. The endocytic matrix. Nature 463:464-473 (2010).
3. Platta, H.W. & Stenmark, H. Endocytosis and signaling. Curr. Opin. Cell Biol. 23: 393-403 (2011).
4. Sigismund, S., Confalonieri, S., Ciliberto, A., Polo, S., Scita, G. & Di Fiore, P.P. Endocytosis and signaling: cell logistics shape the eukaryotic cell plan. Physiol. Rev. 92:273-366 (2012).
5. Lee, J. Y. & Harland, R. M. Endocytosis is required for efficient apical constriction during Xenopus gastrulation. Curr. Biol. 20:253–258 (2010).
6. Mateus, A. M., Gorfinkiel, N., Schamberg, S. & Martinez Arias, A. Endocytic and recycling endosomes modulate cell shape changes and tissue behaviour during morphogenesis in Drosophila. PLoS One 6, e18729 (2011).
7. Fabrowski, P., Necakov, A.S., Mumbauer, S., Loeser, E., Riversi, A., Streichan, S., Briggs, J.A. & De Renzis, S. Tubular endocytosis drives remodeling of the apical surface during epithelial morphogenesis in Drosophila. Nat. Commun. 7:2244 (2013). doi: 10.1038/ncomms3244.
8. Ferguson, S. M. & De Camilli, P. Dynamin, a membrane-remodelling GTPase. Nat. Rev. Mol. Cell. Biol. 13, 75–88 (2012).
9. Chua, J., Rikhy, R. & Lippincott-Schwartz, J. Dynamin 2 orchestrates the global actomyosin cytoskeleton for epithelial maintenance and apical constriction. Proc. Natl Acad. Sci. USA 106, 20770–20775 (2009).