Biology Reference
In-Depth Information
Drosophila
revealed that the target protein Mad was phosphorylated in nerve
terminals
in vivo
and in the nucleus but not in the intervening axon (
Smith,
Machamer, Kim, Hays, &Marques, 2012
). Though other mechanisms were
proposed, one likely mechanism is Mad was dephosphorylated during trans-
port and then reactivated once it reached the soma which may not have been
detected by the FRAP detection methods used. Conceivably, if the growth
factor or neurotrophin is still in the postsorted endosome, the receptor can
be unsilenced by receptor reengagement and/or phosphatase inactivation.
During endocytic sorting, spatially regulated EGF receptor kinase signaling
can be modulated by the endoplasmic reticulum (ER)-associated protein ty-
rosine phosphatase-1B, influencing EGF receptor trafficking and interac-
tions with signaling proteins (
Eden, White, Tsapara, & Futter, 2010
).
Lipid-raft-associated proteins may also potentiate Trk signaling. The
lipid-raft-associated protein, p18, is part of a scaffolding complex that
anchors members of the MAP kinase-ERK signaling pathway to signaling
endosomes (
Nada et al., 2009
) and thus can potentiate Trk signaling at the
endosome. Thus, the Trk receptor lipid raft environment is likely influential
in shaping the Trk endosome signaling profile.
In addition to modifying Trk receptor signaling, lipid rafts may also reg-
ulate communication between signaling endosomes and other organelles in
growth cones with consequences for signaling endosome signaling. Smooth
ER is present throughout dendrites (
Horton & Ehlers, 2003
), axons, and
growth cones (
Merianda et al., 2009
), and recent data indicates that cholesterol
concentrations may regulate close membrane contact sites between the ER
and signaling endosomes. Functionally, close contacts between endosomes
and the ER can mediate the exchange of materials including lipids
(
Toulmay & Prinz, 2011
), which as discussed above may influence Trk sig-
naling complex activity and organization. Close contacts may also exchange
internal solutes, possibly changing the interlumen pH or calcium concentra-
tions (
Lebiedzinska, Szabadkai, Jones, Duszynski, & Wieckowski, 2009;
Levine & Loewen, 2006; Toulmay & Prinz, 2011
), which could then
regulate a number of endosomal factors including neurotrophin-Trk
binding efficiency. Interestingly, unlike BDNF, NT-3 does not generate
retrograde signaling endosomes when bound to TrkB. However, blocking
endosome acidification enables NT3-mediated retrograde transport
(
Harrington et al., 2011
), indicating that the intraluminal environment can
have profound effects on signaling endosome signaling and function.
How do lipids affect signaling endosome trafficking in the growth cone?
Close contacts with the ER in growth cones may also mediate endosomal
