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during development, maintenance, and regeneration, as signaling endosome
dysfunction leads to nervous system disorders and aberrant neuronal patterning
(
Aridor & Hannan, 2000; Jiang et al., 2010; Li et al., 2010; Magalhaes et al.,
2010; Salinas, Bilsland, & Schiavo, 2008
).
Signaling endosomes are generated by a number of different ligands and
their cognate receptors in neurons as well as in less polarized cells. These
ligands include epidermal growth factor (EGF), transforming growth
factor-
b
, Wnt, Nogo, NOTCH-family members, tumor necrosis factor,
and ligands for Toll-like receptors (e.g. see
Disanza, Frittoli, Palamidessi,
& Scita, 2009; Scita & Di Fiore, 2010; Sorkin & von Zastrow, 2009
).
Here, we focus on neurotrophin-generated signaling endosomes and their
potential roles in regulating growth cone motility. However, the emerging
views on local signaling endosome signaling discussed here should be
viewed as concepts employed by cells generally to spatially regulate signal-
specific pathways, and, as such, we fill gaps in local neurotrophin signaling
with data from other cell types as it pertains to common cytoskeletal
processes underlying both nonneuronal cell and neuronal growth cone
motility.
2. SIGNALING ENDOSOME FORMATION
2.1. Receptor-mediated endocytosis
How are signaling endosomes generated in growth cones? In neurons,
signaling endosome development is a multistep process beginning with
the activation of Trk receptors by neurotrophins and the subsequent
endocytosis of neurotrophin-Trk receptor complexes into vesicles
(
Fig. 2.3
). Trk receptors are single-transmembrane domain proteins with
a tyrosine-kinase domain in their cytoplasmic domain. Upon neurotrophin
binding, neurotrophin-mediated dimerization activates Trk receptors by
trans
-phosphorylation (
Huang & Reichardt, 2003; Jing, Tapley, &
Barbacid, 1992; Ullrich & Schlessinger, 1990
). Subsequently, activated
Trk receptors provide docking sites for adaptor proteins that recruit and
activate downstream signaling molecules while still at the plasma
membrane (
Reichardt, 2006
). Single molecule imaging of Cy-3-NGF in
cultured dorsal root ganglion (DRG) neurons suggests activated Trk
receptor complexes are endocytosed by growth cones predominantly in
the central domain. Cy-3-NGF-Trk receptor complexes that form in the
growth cone's peripheral domain initially move randomly on the cell
surface and then move centripetally, by apparently linking to retrograde
