In particular, downregulation of the lipid raft organizing protein Flotillin (also known as Reggie; Otto

and Nichols, 2011) renders neurons insensitive to Sema3A-mediated growth cone collapse (Carcea et al., 2010). There are multiple examples of the need for lipid raft partitioning for directional responsiveness to Selleckchem S3I 201 guidance cues (Guirland and Zheng, 2007), and endocytosis could be one of the cellular responses that differ for receptors found in rafts or not in rafts. These results suggest the possibility that neurons can use an “internalization switch” such that intrinsic differences in signaling responses downstream of common guidance cues regulates extent of endocytosis and thus responsiveness to guidance cues (Carcea et al., 2010). One can also envision how the same cell could throw the internalization switch differently at different developmental junctures, or how different parts of the same neuron could respond differently to the same cues (for example, Polleux and Ghosh, 2002 and Shelly et al., 2011) using an internalization

switch. Many receptors that have more than one ligand show ligand-specific responses upon activation. What could be a cellular mechanism explaining this observation? A recent study of differential signaling outcomes resulting from NGF and NT-3 binding to the TrkA receptor provides a beautiful example (Harrington et al., 2011). NGF and NT-3 both bind and activate TrkA receptor to promote axonal extension (Kuruvilla et al., 2004) and activate E7080 manufacturer also multiple known downstream effectors of TrkA. NT-3 is secreted by intermediate targets of sympathetic neurons and mediates signaling important for local axon extension, while NGF is produced in final target fields of sympathetic neurons and supports neuronal survival via retrograde signaling. Only NGF-induced internalized NGF/TrkA endosomes are capable of eliciting retrograde survival signaling. Harrington et al. (2011) discovered that NGF/TrkA endosomes, but not NT-3/TrkA endosomes, recruit and activate rac1 and cofilin, a microfilament-depolymerizing factor. Activation

of rac1 on early endosomes and activation of cofilin are necessary and sufficient for maturation of TrkA-containing early endosomes to retrogradely-transporting signaling endosomes. The authors also showed that NT-3 binds inefficiently to Trk under acidic environment, such as that in the early endosome, and by a mechanism that remains to be defined, dissociation of NT-3 from TrkA in the endosome prevents recruitment of rac1, even though activation of other signaling cascades is sustained. These data suggest that differential sensitivity to endosomal acidification underlies the differences in the capability of NGF/Trk and NT-3/Trk endosomes to elicit retrograde survival signaling and beautifully highlight the regulatory power of postendocytic events in signaling endosomes.

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