Endocytosis and Signaling An Inseparable Partnership

thus, we will restrict our discussion to the possible physiological relevance of signaling from the endosome. Given the importance of ERKs (and PI3-K) in signaling, 20141 Milan one would predict dramatic effects of the blockade of University of Milan Medical School endocytosis on biological phenotypes. However, in the 20122 Milan few cases where biological end points were measured, The FIRC Institute for Molecular Oncology inhibition of endocytosis did not result in attenuation of 20134 Milan biological effects (Ceresa et al., 1998; Vieira et al., 1996), Italy arguing against a general relevance of endosome-origi-2 Department of Cell Biology and Howard Hughes nated signals. This contribution becomes essential when Medical Institute signals generated at the cell periphery must be translo-Yale University School of Medicine cated over long distances, as in retrograde axonal signal-295 Congress Avenue ing. In this case, intracellular signaling cannot be New Haven, Connecticut 06510 achieved by diffusion and the transport of membrane-bound signaling complexes represents an efficient way to deliver the signal(s) to a physiologically relevant loca-Endocytosis through clathrin-coated pits has long been tion within meaningful time scales. For example, neuro-regarded as a mechanism to switch off plasma mem-trophic factors and their cognate Trk receptors are retro-brane receptor signaling. In this view, trapping of recep-gradely transported from nerve terminals to cell bodies, tors into coated pits is considered mainly a passive where they activate the transcriptional machinery. The phenomenon that occurs via endocytic motifs exposed compartmentalized application of noninternalizable NGF by receptors, either constitutively or following interac-reveals how endocytosis is not required for signaling tion with ligands. Growing evidence, however, suggests from the plasma membrane of the cell bodies to the an important cross-talk between endocytosis and sig-nucleus, but is absolutely necessary for the effects of naling. In this review, we will focus on some of the recent NGF applied to nerve terminals. Application of NGF to advances on the molecular mechanisms that connect distal axons is sufficient to promote survival, an event the machinery of receptor-mediated signaling and endo-that requires NGF-induced PI3-K activity (Kuruvilla et cytosis via clathrin-coated pits. al., 2000). Two different pools of active PI3-K seem in-Signaling from Endosomes and Its Relevance volved in the process. The nerve terminal pool may be While it is clear that active receptors signal from the involved in initiating retrograde transport. A second plasma membrane, they are frequently still in their active pool, likely generated from active endosomal TrkA, is …