Signaling Endosomes and Growth Cone Motility in Axon Regeneration - International Review of Neurobiology - page 42

F-actin flow, to the central domain for endocytosis ( Tani et al., 2005 )
( Fig. 2.3A ). Such observations suggest that cues that locally regulate
retrograde flow could also locally affect endocytosis. Subsequently,
neurotrophin-Trk complexes are endocytosed either by clathrin-
dependent ( Grimes et al., 1996; Howe et al., 2001 ) or a Rac1 and EH-
domain, dynamin-like ATPase, Pincher/EHD4-dependent mechanism
( Daumke et al., 2007; Grimes et al., 1996; Shao et al., 2002; Valdez
et al., 2005 ) into the nascent Trk endosome. Nascent endosomes are then
sorted into signaling endosomes that are retrogradely transported along
axonal microtubules to somas, retained in the growth cone, or shuttled
back to the plasma membrane via the exocytotic pathway (e.g., Fig. 2.2 ).
For neurotrophin-generated signaling endosomes, this process can
originate at the plasma membrane, in the soma, along axons and
dendrites, and in growth cones or synapses, with receptor activation at
each location likely activating distinct signaling pathways ( Goldberg,

2003; Zweifel, Kuruvilla, & Ginty, 2005 ).

2.2. Sorting and signaling
How are nascent Trk endosomes sorted? Once endocytosed, nascent Trk
endosomes are differentially sorted and trafficked based on their
colocalization with Ras superfamily members, the Rab GTPases. The Rabs
comprise a family of approximately 70 members that regulate virtually all
vesicular trafficking, transport, and membrane fusion events ( Hutagalung
& Novick, 2011 ). In their GTP-bound, active form, the Rab GTPases re-
cruit specific effector proteins to vesicle membranes to regulate vesicle for-
mation, actin- and tubulin-dependent vesicular transport, and membrane
fusion. In neurotrophin trafficking, the best characterized Rabs are Rab5,
-7, and -11. Nascent Trk vesicles are thought to be shuttled initially into
early endosomes by Rab5, which mediates the fusion of endocytic
vesicles to form the early endosome. Activated Trk receptors colocalize
with Rab5 and the Rab5 effector early endosome antigen-1 (EEA1)
( Donmez, Rajagopal, Jeong, & Patel, 2007; Rantanen, Lehtio,
Rajagopal, Rubens, & Goldman, 2007 ) or APPL1 and APPL2
( Miaczynska et al., 2004 ). Rab5 localizes to the plasma membrane and
can mediate the conversion of both clathrin- and nonclathrin-dependent
endosomes into early endosomes ( Disanza et al., 2009 ), suggesting Rab5
may be attracted to activated Trk receptors during the initial stages of
vesicle endocytosis.