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associated with lamellar and filopodia protrusion ( Burridge & Wennerberg,
2004; Hall & Nobes, 2000 ). Rac coordinates branched actin assembly
underlying lamellipodia and membrane ruffles though various effectors,
including the ARP2/3 nucleation complex, whereas Cdc42 regulates
bundled actin filament assembly underlying filopodia through various
downstream effectors, including formins regulated by Ena/Vasp proteins
( Lowery & Van Vactor, 2009 ). Hence, the precise spatiotemporal
regulation of Rac and Cdc42 activation is critical to directing polarized
cytoskeletal assembly driving lamellar and filopodial protrusion in the
growth cone.
Interestingly, the distribution of Rho-family GTPases is mediated in part
by directed membrane trafficking ( Bloom & Morgan, 2011 ), including Trk
signaling endosomes. Rac localization to TrkB signaling endosomes in the
leading lamellar process of GCPs is critical to the chemotactic response to
BDNF in vivo ( Zhou et al., 2007 ). In nonneuronal cells, Rab5 early signaling
endosomes regulate cell migration by physically transporting Rac
( Palamidessi et al., 2008 ) and Cdc42 ( Osmani, Peglion, Chavrier, &
Etienne-Manneville, 2010 ) to the leading lamellar edge to regulate protru-
sion. Similarly, PDGF receptor activation directs endosome-bound Cdc42
and Rac to the cell periphery prior to new lamellar and filopodial protrusion
( Huang, Satchell, Duhadaway, Prendergast, & Laury-Kleintop, 2011 ). Trk
endocytosis and transport is itself Rac-dependent, and Pincher-generated
signaling endosomes require Rac activity ( Valdez et al., 2007 ). Rac1 and
the actin-severing protein cofilin are recruited to active TrkA signaling
endosomes, and this association appears to be necessary to regulate retro-
grade NGF signaling and survival. This “TrkA-Rac1-cofilin actin-severing
module” is necessary and sufficient for NGF/TrkA signaling endosome
retrograde transport and survival signaling ( Harrington et al., 2011 ). Thus,
signaling endosome localization may regulate growth cone morphology by
localizing cytoskeletal effectors.
Whether signaling endosomes regulate Rac and Cdc42 activity directly
or simply act as a transport platform for their localization to specific regions
of the growth cone remains to be determined. Phospholipids, produced by
PI3-K, can serve as effectors that stimulate the Rho-family GTPases Rac and
Cdc42 ( Affolter & Weijer, 2005; Bokoch, Vlahos, Wang, Knaus, &
Traynor-Kaplan, 1996; Hawkins et al., 1995 ), suggesting signaling
endosomes could transport and activate Rac and Cdc42. However,
whether neurotrophin-activated PI3-K activity regulates Rac and Cdc42
on signaling endosomes
is currently unknown. Moreover,
the direct
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