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in vitro
and
in vivo
(
Altick et al., 2009; Cui et al., 2007
). Together, these data
suggest that signaling endosomes undergo intracellular repackaging in the
growth cone or synapse, possibly influenced by the number of
neurotrophins and neurotrophin receptors per endosome.
2.3. Lipids and signaling
How do lipids influence Trk signaling endosomes? Studies suggest the
endosomal lipid environment also regulates endosome signaling. Prior to
endocytosis, Trk receptors are often found in sphingolipid-cholesterol lipid
rafts (
Kamiguchi, 2006; Simons & Gerl, 2010
), and neurotrophin activation
of Trk receptors may stimulate Trk receptors to move into lipid rafts (
Pryor
et al., 2012
). Lipid rafts are dynamic microdomains in the plasma membrane
(
Dietrich, Yang, Fujiwara, Kusumi, & Jacobson, 2002; Kusumi, Koyama-
Honda, & Suzuki, 2004
) formed by the preferential association of
cholesterol with saturated fatty acids and glycosphingolipids (
Simons &
Vaz, 2004
). Lipid rafts are concentrated in growth cones and mediate
chemotropic guidance (
Guirland, Suzuki, Kojima, Lu, & Zheng, 2004;
Ibanez, 2004; Kamiguchi, 2006
), possibly by locally stabilizing dynamic
microtubules (
Pryor et al., 2012
) and organizing signaling molecule
complexes (
Golub, Wacha, & Caroni, 2004; Helms & Zurzolo, 2004;
Simons & Toomre, 2000
) that can modulate the activity of cytoskeletal
effectors downstream of activated Trk receptor
signaling,
like Akt
(
Grider, Park, Spencer, & Shine, 2009
).
Lipid rafts can also be highly enriched in signaling molecules such as
glycosylphosphatidylinositol-anchored proteins, kinases, and phosphatases
(
Pike, 2003
), which may regulate Trk receptor kinase activity (e.g.,
Fig. 2.3A
). For instance, both in PC12 cells and in DRG neurons, NGF
both increased TrkA in lipid rafts and locally stabilized microtubules in lipid
rafts with activated Trk receptors. However, activated phospho-TrkA was
undetectable in lipid-raft-associated endosomes, suggesting that activated
TrkA was sorted into lipid rafts upon activation, dephosphorylated, and then
endocytosed into nonsignaling endosomes by a microtubule-dependent
mechanism (
Pryor et al., 2012
).
Local Trk silencing by lipid-raft-associated phosphatases may play a role
in signaling endosome sorting in growth cones by preventing the attraction
of other signaling molecules to the nascent endosome (
Scita & Di Fiore,
2010
). Perhaps, silencing is preferable in some cases to facilitate transport.
Recent
studies on bone morphogenic protein (BMP) endosomes
in
