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(
Zoncu et al., 2009
). Trk activation can also regulate microtubule stability
through PI3-K-dependent regulation of glycogen synthase kinase 3-beta
activity (
Zhou & Snider, 2006
). Whether neurotrophin-activated signaling
endosomes regulate Rab5-effector relationships or microtubule stability in
growth cones through PI3-K activity remains to be determined. In addition
to second messenger signaling, neurotrophin signaling endosome activation
of PI3-K and PLC
g
can potentially modify the phospholipid profile of the
signaling endosome (
Eyster, 2007
).
How much of the nascent endocytic vesicle generated at the distal
terminal or growth cone by initial receptor binding ends up in the active
signaling endosome? In some cases, neurotrophins appear to be endocytosed
directly into MVBs by Pincher-generated Trk-MVBs for retrograde trans-
port (
Philippidou et al., 2011
). However, as mentioned above, MVBs appear
to be rare in the axons of both PNS and CNS neurons
in vivo
. On the other
hand, though signaling endosomes are often described as single entities
defined by their relationship to a few markers, that is, activated Trks, Rabs,
Rab effectors, and signaling complex components of the MAPK, PLC
g
, and
PI3-K pathways, signaling endosomes are not likely solitary entities gener-
ated at the plasma membrane that simply acquire a compliment of signaling
molecules and are then transported to the nucleus where they can affect gene
expression. Instead, existing data argue that signaling endosomes are more
likely a population of dynamic and unique signaling platforms that can take
on many forms in the combination of associated signaling complexes and
their interrelationships with other signaling endosomes and organelles
(
Scita & Di Fiore, 2010
).
Alternatively, some evidence suggests that signaling endosomes are in
fact unnecessary (
MacInnis & Campenot, 2002
). For instance, neurotrophin
signaling may be propagated like a wave (
Kholodenko, 2003
). In compart-
mentalized cultures, tyrosine phosphorylation is detectable in the soma
centimeters away from the neurotrophin-stimulated terminal within a fewmi-
nutes (
MacInnis, Senger, & Campenot, 2003
). Such rapid signal propagation
cannot be accounted for by molecular motors moving at a few microns per
second (
Hill, Plaza, Bonin, &Holzwarth, 2004
), supporting the idea that neu-
rotrophin signaling endosome signaling is much more complex and may ac-
tually require the oscillatory propagation of neurotrophin-generated signals,
e.g. via ERKs (
Kholodenko, 2007; Maeda et al., 2004
), through many
intracellular compartments. Additionally, the
in vivo
localization of
radiolabeled neurotrophins suggests that neurotrophins are shuttled between
many compartments in the cell including the golgi, mitochondria, nucleus,
