Biology Reference
In-Depth Information
sequences on any integrins (although the
b
4 integrin has a fibronectin type
III region on its cytoplasmic tail (
Spinardi, Ren, Sanders, & Giancotti,
1993
)). Alternatively,
b
1 integrins possess two NPXY motifs in their cyto-
plasmic domains which are involved in endocytosis and trafficking processes
(
Maginnis et al., 2008
); however, it has not been determined whether these
are important for neuronal traffic. Trk receptors also possess the NPXY mo-
tif, and recent evidence suggests that they share similar trafficking pathways
with integrins. TrkA and
b
1 integrins both traffic anterogradely by trans-
cytosis regulated by the recycling endosome marker Rab11 (
Ascano
et al., 2009; Eva et al., 2010
), and they accumulate on the cell surface to-
gether in lipid rafts in DRG neurons and PC12 cells (
Ichikawa et al.,
2009
). We first chose to investigate integrin traffic via Rab11 in adult
DRG axons, as Rab11 is involved in trafficking
b
1 integrins in cancer cells
to locations that are distant from the cell body (
Caswell et al., 2008
), and
integrins are transported readily into sensory axons. This was contemporary
with the study by Ascano et al. that identified a role for Rab11 in the trans-
cytotic transport of TrkA in sympathetic axons. We found that integrins
could be internalized at the cell body before moving into axons; however,
we also found that anterograde transport of integrins via Rab11 was slow,
and we observed rapidly moving integrin vesicles that were not positive
for Rab11 (
Fig. 3.1
B). We have recently found that the rapidly moving ves-
icles are marked by ARF6 (
Eva et al., 2012
;
Fig. 3.1
B). ARF6 is another
marker of recycling endosomes, which has some overlap with Rab11.
It is not known if Trk receptors also traffic via ARF6; however, ARF6 has
been associated with trafficking via the sorting protein sortilin (
Li et al.,
2007
), and this is implicated in axonal trafficking of all three neurotrophin
receptors in DRG neurons (
Vaegter et al., 2011
). We have also observed
colocalization between sortilin and
b
1 integrins in differentiated PC12 cells
(Richard Eva, James Fawcett, unpublished findings). Of the three Trk re-
ceptors, TrkB has received the most attention regarding its mechanism of
axonal traffic and is reported to traffic via sortilin (
Vaegter et al., 2011
),
JIP3/kinesin-1 (
Huang et al., 2011
) and Rab27b (
Arimura et al., 2009
).
Are these mechanisms related? We have already mentioned the overlap be-
tween sortilin and the ARF6 pathways, and it is known that ARF6 interacts
with JIP3 to modulate its interaction with kinesins and the dynein/dynactin
complex, resulting in regulation of the direction of transport during cytoki-
nesis (
Montagnac et al., 2009
), so there may be some ARF6-dependent con-
trol of TrkB trafficking via JIP3. Rab27b was identified as a regulator of
TrkB trafficking in a complex of Slp1/Rab27B/CRMP-2. This complex
