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binds to kinesin-1-mediating anterograde axonal transport (
Arimura et al.,
2009
). Interestingly, the authors also found that TrkB coimmunprecipitates
with Rab8. Rab8 is involved in anterograde membrane traffic in hippocam-
pal neurons in culture (
Huber, Dupree, & Dotti, 1995
), and is found in dy-
namic actin-rich membrane structures such as filopodia and lamellipodia
(
Peranen, 2011
). The interaction with TrkB may also be in a complex, be-
cause Rab8 binds directly to Slp1 (
Hattula et al., 2006; Hokanson &
Bretscher, 2012
) and is noteworthy because trafficking via Rab8 has some
commonality with trafficking via both Rab11 and ARF6. Further, Rab8
is linked with traffic via EHD1/Mical-L1 (
Sharma, Giridharan, Rahajeng,
Naslavsky, &Caplan, 2009
). This is an endocytic regulatory protein that also
interacts with ARF6 (
Rahajeng, PanapakkamGiridharan, Cai, Naslavsky, &
Caplan, 2012
) and is involved in recruitment to endosomes. EHD1 is in-
volved in axonal targeting of L1/NgCAM (
Lasiecka et al., 2010
), and also
regulates the endosomal transport of
b
1 integrins in nonneuronal cells to
control cell migration (
Jovic et al., 2007
).
There is therefore a group of proteins implicated in regulating axonal
traffic that can all be linked to one another through their reported interac-
tions: Rab11, ARF6, Rab27/Slp1/Rab8, and EHD1/MICAL-L1. It may
be important to determine a “central regulator” of these molecules, and it
has recently been proposed that Rab35 is a critical upstream regulator of
MICAL-L1 and Arf6, and that MICAL-L1 and Arf6 regulate Rab8 function
(
Rahajeng et al., 2012
). Rab35 regulates neurite outgrowth in PC12 cells by
controlling ARF6 activity (
Kobayashi & Fukuda, 2012
), but has not yet
been identified in primary axons. However, consistent with a role for
ARF6 as a key molecule, we have found that the direction of axonal integrin
traffic can be manipulated by expression of ARF6 GEFs and GAPs, with
overexpression of the ARF6 GEFs, EFA6, or ARNO resulting in increased
retrograde transport, and expression of the GAP ACAP1 resulting in
increased anterograde transport (
Eva et al., 2012
).
3.3. Trafficking at the growth cone
Understanding trafficking of integrins into axons will help to identify strat-
egies to control integrin transport; however, it is also important to under-
stand how integrins are trafficked into the growth cone surface, and how
they are recycled once there because these processes are critically involved
in the control of migratory behavior. The majority of neuronal integrins re-
side in an endosomal fraction (
Eva et al., 2010
), and it is well known that
