Drosophila Photoreceptor Axon Guidance and Targeting Requires the Dreadlocks SH2/SH3 Adapter Protein

Garrity, Paul; Rao, Yong; Salecker, Iris; McGlade, Jane; Pawson, Tony; Zipursky, S. Lawrence

doi:10.1016/s0092-8674(00)81231-3

Cited by 246 publications

(197 citation statements)

References 55 publications

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“…The Drosophila homolog of Nck, Dreadlocks, has been shown to play an important role during axonal navigation in photoreceptor cells (Garrity et al, 1996), but the role of Nck in mammalian cells is unclear. The SH2 domain of Nck has previously been shown to bind to phosphorylated receptors and cytoplasmic tyrosine kinases as well as to IRS-1 (reviewed in Birge et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

1998

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Tek/Tie2 is an endothelial cell-speci®c receptor tyrosine kinase that has been shown to play a role in vascular development of the mouse. Targeted mutagenesis of both Tek and its agonistic ligand, Angiopoietin-1, result in embryonic lethality, demonstrating that the signal transduction pathway(s) mediated by this receptor are crucial for normal embryonic development. In an attempt to identify downstream signaling partners of the Tek receptor, we have used the yeast two-hybrid system to identify phosphotyrosine-dependent interactions. Using this approach, we have identi®ed a novel docking molecule called Dok-R, which has sequence and structural homology to p62 dok and IRS-3. Mapping of the phosphotyrosine-interaction domain within Dok-R shows that Dok-R interacts with Tek through a PTB domain. Dok-R is coexpressed with Tek in a number of endothelial cell lines. We show that coexpression of Dok-R with activated Tek results in tyrosine phosphorylation of Dok-R and that rasGAP and Nck coimmunoprecipitate with phosphorylated Dok-R. Furthermore, Dok-R is constitutively bound to Crk presumably through the proline rich tail of Dok-R. The cloning of Dok-R represents the ®rst downstream substrate of the activated Tek receptor, and suggests that Tek can signal through a multitude of pathways.

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Section: Discussionmentioning

confidence: 99%

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

1998

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“…One could easily envision how a combination of relocalization of Pak (mediated at least in part by Nck, which can bind to tyrosine phosphorylated proteins via its SH2 domain) and localization of activated, GTP-bound Rho-family GTPases could generate sharp spatial gradients in Pak activity. In this light it is interesting that Nck is present in the growth cones of Drosophila neurons, where Nck mutation has been shown to lead to defects in axon path®nding and targeting (Garrity et al, 1996). Nck can bind via its SH2 domain to the Eph receptor, which is known to play a role in axon guidance (Holland et al, 1997;Stein et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…An intriguing candidate is the recently described mig-2 protein, which was isolated in C. elegans as a mutant a ecting axon migration (Zipkin et al, 1997). The axon phenotype of mig-2 is suggestive in light of the axon migration and path®nding phenotype of Nck mutants in Drosophila (Garrity et al, 1996). Activated mig-2 mutations a ect many more cells than do mig-2 null mutations, and double mutants carrying mig-2 null mutations along with weak mutations in unc-73, a putative exchange factor for small GTPases, showed new phenotypes besides defects in cell migration.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of activation of Pak1 kinase by membrane localization

Mayer

1999

Oncogene

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Pak kinases are a family of serine/threonine protein kinases homologous to Ste20p of yeast. Paks can be activated in vivo and in vitro by binding to GTP-bound Cdc42 and Rac1, members of the Rho family of small GTPases implicated in regulating the organization of the actin cytoskeleton. We have previously reported that the SH2/SH3-containing adaptor protein Nck binds Pak kinase through its second SH3 domain. Pak1 can be targeted to the membrane by Nck in response to tyrosine phosphorylation, and membrane association of Pak1 is su cient to increase its speci®c activity. The mechanism whereby Pak is activated by membrane localization, however, is unknown. We show here that expression of three proteins that inhibit Rho-family GTPases by di erent mechanisms (RhoGDI, Bcr and D57Y Cdc42) all block the activation of Pak by a membrane-targeted Nck SH3 domain, demonstrating that the in vivo activation of Pak1 induced by membrane localization is dependent on Rho-family GTPases. This implies that Pak activity can be regulated in cells both by the level of GTP loading of various Rho-family GTPases and the local concentration of Pak relative to these GTPases. Our data also suggest the existence of Rho-family GTPases in addition to Cdc42 and Rac1 that can activate Pak on membranes.

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“…Although the binding site for PI3-kinase on c-Cbl has not been mapped in detail, it too may bind to the C-terminal half of c-Cbl (Meisner et al, 1995). Drosophila homologues of 14-3-3, Nck and PI3-kinase exist but would not be predicted to interact with D-Cbl (Clemens et al, 1996;Garrity et al, 1996;Leevers et al, 1996;Skoulakis and Davis, 1996).…”

Section: Truncation Of D-cbl Relative To C-cblmentioning

confidence: 99%

D-Cbl, the Drosophila homologue of the c-Cbl proto-oncogene, interacts with the Drosophila EGF receptor in vivo, despite lacking C-terminal adaptor binding sites

Hime

Dhungat

et al. 1997

Oncogene

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The c-Cbl proto-oncogene encodes a multidomain phosphoprotein that has been demonstrated to interact with a wide range of signalling proteins. The biochemical function of c-Cbl in these complexes is, however, unclear. Recent studies with the C. elegans Cbl homologue, sli-1, have suggested that Cbl proteins may act as negative regulators of EGF receptor (EGFR) signalling. As the EGFR and other protein tyrosine kinase receptor signalling pathways are highly conserved between insects and vertebrates, we sought a Drosophila homologue of cCbl for a detailed genetic analysis. We report here that Drosophila melanogaster has a single gene, D-cbl, that is homologous to c-cbl. We ®nd that D-cbl encodes a 52 kDa protein that has a high degree of similarity to cCbl and SLI-1 across novel phosphotyrosine-binding (PTB) and RING ®nger domains. Surprisingly, however, D-Cbl is C-terminally truncated relative to c-Cbl and SLI-1 and consequently is unable to bind SH3-domain containing adaptor proteins, including the Drosophila Grb2 homologue, Drk. Although the D-Cbl protein lacks Drk binding sites it can nevertheless associate with a tyrosine phosphorylated protein, or is itself tyrosine phosphorylated in an DER dependent manner and associates with activated Drosophila EGF receptors (DER) in vivo. Consistent with a role for D-Cbl in DER dependent patterning in the embryo and adult, DCbl is expressed at a high level in early embryos and throughout the imaginal discs in third instar larvae. This study forms the basis for future genetic analysis of DCbl, aimed at gaining insights into the role of Cbl proteins in signal transduction.

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Drosophila Photoreceptor Axon Guidance and Targeting Requires the Dreadlocks SH2/SH3 Adapter Protein

Cited by 246 publications

References 55 publications

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

Mechanism of activation of Pak1 kinase by membrane localization

D-Cbl, the Drosophila homologue of the c-Cbl proto-oncogene, interacts with the Drosophila EGF receptor in vivo, despite lacking C-terminal adaptor binding sites

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