Trio Combines with Dock to Regulate Pak Activity during Photoreceptor Axon Pathfinding in Drosophila

Newsome, Timothy P.; Schmidt, Susanne; Dietzl, Georg; Keleman, Krystyna; Åsling, Bengt; Debant, Anne; Dickson, Barry J.

doi:10.1016/s0092-8674(00)80838-7

Cited by 302 publications

(280 citation statements)

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“…Among other structural features, the Drosophila Trio contains a motif of DH-PH ± DH-PH tandem domains, the characteristic feature of GEFs speci®c for the Rho family GTPases. It was shown that Trio localizes at the growth cone membrane and that the trio mutant disrupted the photoreceptor axon projection patterns (Newsome et al, 2000), defects similar to those seen in both Pak and dock mutants (Garrity et al, 1996;Hing et al, 1999). This function of Trio in axon guidance depended upon its GEF activity, since mutation in one of two GEF domains of Trio completely abolished the Trio function.…”

Section: Nck Links Cell Surface Receptors To the Actin Cytoskeletonmentioning

confidence: 91%

“…This function of Trio in axon guidance depended upon its GEF activity, since mutation in one of two GEF domains of Trio completely abolished the Trio function. Newsome et al (2000) went on to identify the downstream signaling events activated by the Drosophila Trio, and showed that Trio activated Rac and Mtl (Mig-two-like), but not Cdc42 and Rho, which in turn bound Pak and induced membrane ru ing and lamellipodium formation. These results indicated that the Trio-Rac-Dock-Pak pathway functions in the control of growth cone guidance and motility.…”

Section: Nck Links Cell Surface Receptors To the Actin Cytoskeletonmentioning

confidence: 99%

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Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton

2001

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In response to extracellular signals, cell surface receptors engage in connections with multiple intracellular signaling pathways, leading to the cellular responses such as survival, migration, proliferation and di erentiation. Thè pY?SH2/SH3?e ector' connection is a frequently used scheme by many cell surface receptors, in which SH2/SH3-containing adapters connect protein tyrosine phosphorylation to a variety of downstream e ector pathways. Following the initial landmark ®nding that Grb2 adapter links the receptors to the Ras pathway leading to DNA synthesis, recent studies have revealed that the biological function of the SH2/SH3 adapter Nck/Dock is to link cell surface receptors to the actin cytoskeleton. For example, in the evolutionarily-conserved signaling network, GEF-Rac-Nck-Pak, Nck`®xes up' the interaction of Pak with its upstream activator, Rac. The activated Pak then regulates the cytoskeletal dynamics. The fact that the majority of the more than 20 Nck-SH3-associated e ectors are regulators of the actin cytoskeleton suggests that Nck/Dock regulates, via binding to distinct e ectors, various cell type-speci®c motogenic responses. This review focuses on our current understanding of Nck/Dock function. Due to the number and complexity of the terminologies used in this review, à Glossary of Terms' is provided to help reduce confusions. Oncogene (2001) 20, 6403 ± 6417.Keywords: Src-homology domains; adapters; tyrosine kinases; signal transduction; cytoskeleton The SH2/SH3 adapters The src-homology 2 (SH2) and src-homlogy 3 (SH3) domains are protein ± protein interaction modules, found in a variety of structurally and functionally distinct signaling molecules, including protein tyrosine kinases/phosphatases, lipid kinase/phosphatase, guanine nucleotide exchange factors/GTPase activation proteins, docking proteins/adapters, cytoskeletal binding proteins and even transcription factors (Pawson, 1995;Mayer, 1999). Except for the terminology, SH2 and SH3 domains share no other common features regarding their structures, binding speci®city, and cellular targets. SH2 domains enable their host proteins to form complexes with phosphotyrosine (pY) proteins by binding to pY residues within these proteins. The stability and speci®city of the binding also depend upon the additional three to six amino acid residues immediately carboxyl to the pY residue, pY-(X) 3 ± 6 . Therefore, SH2 domains from di erent host molecules bind di erent pY-containing peptides. SH3 domains bind proline-rich segments of target molecules with a minimum consensus of P-x-x-P (Mayer, 2001). Each proline is often preceded by an aliphatic amino acid residue, and the aliphatic-proline pair binds to a hydrophobic pocket on SH3 domains. A major di erence between the SH2-pY binding and SH3-PxxP interactions is that the former is always transiently induced by extracellular signals, whereas the latter is often, but not always, constitutive. For instance, the SH2 domain of the adapter protein Grb2 only binds to tyrosine phosphorylated/activated EGFR, whe...

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Section: Nck Links Cell Surface Receptors To the Actin Cytoskeletonmentioning

confidence: 91%

Section: Nck Links Cell Surface Receptors To the Actin Cytoskeletonmentioning

confidence: 99%

Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton

2001

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“…Trio interacts with a receptor phosphatase, LAR, and potentiates the phenotype of LAR mutants (Bateman et al 2000). Trio also interacts with Dock to activate rac and PAK in photoreceptor axon guidance (Newsome et al 2000).…”

Section: Rho Gtpases: Organizers Of Actin Structuresmentioning

confidence: 99%

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Meyer

Feldman

2002

Journal of Neurochemistry

172

108

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Actin-based motility is critical for nervous system development. Both the migration of neurons and the extension of neurites require organized actin polymerization to push the cell membrane forward. Numerous extracellular stimulants of motility and axon guidance cues regulate actin-based motility through the rho GTPases (rho, rac, and cdc42). The rho GTPases reorganize the actin cytoskeleton, leading to stress fiber, filopodium, or lamellipodium formation. The activity of the rho GTPases is regulated by a variety of proteins that either stimulate GTP uptake (activation) or hydrolysis (inactivation). These proteins potentially link extracellular signals to the activation state of rho GTPases. Effectors downstream of the rho GTPases that directly influence actin polymerization have been identified and are involved in neurite development.The Arp2/3 complex nucleates the formation of new actin branches that extend the membrane forward. Ena/VASP proteins can cause the formation of longer actin filaments, characteristic of growth cone actin morphology, by preventing the capping of barbed ends. Actin-depolymerizing factor (ADF)/cofilin depolymerizes and severs actin branches in older parts of the actin meshwork, freeing monomers to be re-incorporated into actively growing filaments. The signaling mechanisms by which extracellular cues that guide axons to their targets lead to direct effects on actin filament dynamics are becoming better understood. Keywords: actin-depolymerizing factor (ADF)/cofilin, actinrelated protein Arp2/3, ena/VASP, LIM kinase, rho GTPase.

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“…Recently Trio, a unique GEF that has binding domains for both Rac and Rho, has been studied in detail in Dro-sophila (Awasaki et al, 2000;Bateman et al, 2000;Liebl et al, 2000;Newsome et al, 2000). Trio activates Rac selectively by its GEF1 domain, and the GEF2 domain shows specificity for Rho (Debant et al, 1996).…”

Section: Balance Between Rac and Rhomentioning

confidence: 99%

Regulation of neurotrophin‐induced axonal responses via Rho GTPases

Özdinler

Erzurumlu

2001

J of Comparative Neurology

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Nerve growth factor (NGF) and related neurotrophins induce differential axon growth patterns from embryonic sensory neurons. In wholemount explant cultures of embryonic rat trigeminal ganglion and brainstem or in dissociated cell cultures of the trigeminal ganglion, exogenous supply of NGF leads to axonal elongation, whereas neurotrophin-3 (NT-3) treatment leads to short branching and arborization. Axonal responses to neurotrophins might be mediated via the Rho GTPases. To investigate this possibility, we prepared wholemount trigeminal pathway cultures from E15 rats. We infected the ganglia with recombinant vaccinia viruses that express GFP-tagged dominant negative Rac, Rho, or constitutively active Rac or treated the cultures with lysophosphatitic acid (LPA) to activate Rho. We then examined axonal responses to NGF by use of the lipophilic tracer DiI. Rac activity induced longer axonal growth from the central trigeminal tract, whereas the dominant negative construct of Rac eliminated NGF-induced axon outgrowth. Rho activity also significantly reduced, and the Rho dominant negative construct increased, axon growth from the trigeminal tract. Similar alterations in axonal responses to NT-3 and brainderived neurotrophic factor were also noted. Our results demonstrate that Rho GTPases play a major role in neurotrophin-induced axonal differentiation of embryonic trigeminal axons. KeywordsRac; Rho; trigeminal axon growth; NGF; BDNF; viral vectors Primary sensory neurons of the dorsal root and trigeminal (TG) ganglia depend on targetreleased neurotrophins for survival and express specific Trk receptors (McMahon et al., 1994;Wright and Snider, 1995;Conover and Yancopoulos, 1997;Davies, 1997, Davies, 1998Enokido et al., 1999;Huang et al., 1999b). Recent studies also suggest that neurotrophins play a major role in axonal differentiation (Hoyle et al., 1993;Lentz et al., 1999;Ulupinar et al., 2000a; see also Gallo and Letourneau, 2000, for a review). During axonal development, elongation and retraction of growth cones are all related to the arrangement of actin cytoskeleton (for reviews, see Lin et al., 1994;Hall, 1998;Gallo and Letourneau, 2000). The Rho family of GTPases is known to play a major role in this process (for reviews, see Luo et al., 1997;Tapon and Hall, 1997; Aspenstrom, 1999;Mueller, 1999;Song and Poo, 1999;Bishop and Hall, 2000).Members of the family (Cdc42, Rho, and Rac) are either found in the GTP-bound active state or the GDP-bound inactive state (for reviews, see Van Aelst and D'Souza-Schorey, 1997;Mackay and Hall, 1998;Hall 1999;Kjoller and Hall 1999;Bishop and Hall, 2000). Relative abundance of active Rho and Rac might regulate growth cone behavior during axon navigation (Mueller, 1999). Dominant negative and constitutively active versions of Rho GTPases have been used to study their role in axonal arborization (Threadgill et al., 1997;Nakayama et al., 2000), dendritic growth (Threadgill et al., 1997; Ruchoeft et al., 1999;Nakayama et al., 2000;Li et al., 2000), neuronal remodeling (Luo e...

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Trio Combines with Dock to Regulate Pak Activity during Photoreceptor Axon Pathfinding in Drosophila

Cited by 302 publications

References 50 publications

Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton

Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton

Signaling mechanisms that regulate actin‐based motility processes in the nervous system

Regulation of neurotrophin‐induced axonal responses via Rho GTPases

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