Biology Reference
In-Depth Information
Pryor,McCaffrey, Young, &Grimes, 2012
). Finally, Trk activation is linked to
threemain intracellular signaling cascades via awide variety of adaptor proteins,
including mitogen-activated kinase (MAPK) (
Howe et al., 2001
),
phospholipase C-gamma (PLC
g
)(
Ming et al., 1999
), and phosphoinositol-
3-kinase (
Quinn & Wadsworth, 2008
), further emphasizing the possibility
that each signaling endosome, with varying numbers of neurotrophin
cargoes and receptors, likely has a distinct molecular and signaling profile.
Thus, understanding the early signaling endosome signaling profiles and
how different signaling profiles relate to the Rab GTPases is an important
next step to understand signaling endosome sorting in growth cones.
Do growth cones simplify signaling endosome sorting by repackaging?
Instead of trying to sort endosomes based on an unlimited number of signal-
ing profiles, perhaps cells repackage nascent neurotrophin endosomes and
their associated lipid and protein components into a more uniform or distinct
signaling endosome classes? Under this scenario and in the simplest context,
active ligand-receptor complexes may be sorted into Rab5 early endosomes
for retrograde transport, inactive receptors into Rab11 recycling endosomes
for a return trip to the plasma membrane, and dysfunctional receptors into
Rab7 late endosomes for lysosomal degradation.
Supporting a repackaging model, the signaling profile likely changes after
Trk endocytosis since neurotrophin-receptor complexes at the plasma
membrane and neurotrophin complexes in signaling endosomes mediate
distinct cellular behaviors. For instance, TrkA activation and endocytosis
are necessary for survival, signaling, and differentiation (
Zhang,
Moheban, Conway, Bhattacharyya, & Segal, 2000; Zweifel et al., 2005
)
but not axon growth
per se
(
Zweifel et al., 2005
). NGF and NT3 elicit
different responses in postganglionic sympathetic neurons through
differential control of TrkA internalization and trafficking (
Kuruvilla, Ye,
& Ginty, 2000
). NGF induces TrkA endocytosis followed by retrograde
transport of signaling endosomes to the soma. In contrast, NT3
phosphorylates surface TrkA to a similar extent as NGF, but NT-3/TrkA
is not endocytosed. Moreover, surface and endosomal Trks appear to
activate different sets of signaling molecules (
von Zastrow & Sorkin,
2007
). At the plasma membrane, NGF-TrkA can activate Ras transiently,
whereas endosomal NGF-TrkA signaling leads to sustained Rap1 and
MAPK pathway activation (
Wu, Lai, & Mobley, 2001
). Endosomes
immediately after endocytosis can vary dramatically in size and
complexity, but recent studies suggest that uniformly sized, single lumen
vesicles are the primary retrograde neurotrophin signaling endosome
