Abelson tyrosine kinase is required to transduce midline repulsive cues

Hsouna, Anita; Kim, You Seung; VanBerkum, Mark F. A.

doi:10.1002/neu.10232

Cited by 44 publications

(63 citation statements)

References 74 publications

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“…For this analysis, we examined the ISNb motor axons ( Figure 7A) rather than the CNS midline, as Abl acts in both positive and negative capacities during midline guidance (Hsouna et al 2003;Forsthoefel et al 2005), transducing midline repulsive cues as well as attractive cues, which would complicate interpretation of epistasis experiments. Abl plays a more straightforward role for ISNb motor axons, regulating the extent of ISNb motorneuron projection into its multiple muscle targets (Wills et al 1999).…”

Section: Resultsmentioning

confidence: 99%

Parallel Genetic and Proteomic Screens Identify Msps as a CLASP–Abl Pathway Interactor in Drosophila

Lowery

Lee²,

Lu³

et al. 2010

Genetics

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Regulation of cytoskeletal structure and dynamics is essential for multiple aspects of cellular behavior, yet there is much to learn about the molecular machinery underlying the coordination between the cytoskeleton and its effector systems. One group of proteins that regulate microtubule behavior and its interaction with other cellular components, such as actin-regulatory proteins and transport machinery, is the plus-end tracking proteins (MT1TIPs). In particular, evidence suggests that the MT1TIP, CLASP, may play a pivotal role in the coordination of microtubules with other cellular structures in multiple contexts, although the molecular mechanism by which it functions is still largely unknown. To gain deeper insight into the functional partners of CLASP, we conducted parallel genetic and proteome-wide screens for CLASP interactors in Drosophila melanogaster. We identified 36 genetic modifiers and 179 candidate physical interactors, including 13 that were identified in both data sets. Grouping interactors according to functional classifications revealed several categories, including cytoskeletal components, signaling proteins, and translation/RNA regulators. We focused our initial investigation on the MT1TIP Minispindles (Msps), identified among the cytoskeletal effectors in both genetic and proteomic screens. Here, we report that Msps is a strong modifier of CLASP and Abl in the retina. Moreover, we show that Msps functions during axon guidance and antagonizes both CLASP and Abl activity. Our data suggest a model in which CLASP and Msps converge in an antagonistic balance in the Abl signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Parallel Genetic and Proteomic Screens Identify Msps as a CLASP–Abl Pathway Interactor in Drosophila

Lowery

Lee²,

Lu³

et al. 2010

Genetics

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“…In Drosophila robo mutants, too many axons cross and recross the midline (5). Several molecules have been implicated in the Robo signaling pathway, including the actin binding protein Enabled (6,7), the tyrosine kinase Abelson (Abl) (6,8,9), and the Ras͞Rho GEF Son of Sevenless (10,11). Nevertheless, our understanding of the signal-transduction mechanism leading from Slit͞Robo to cytoskeleton rearrangement during repulsive axon guidance remains incomplete.…”

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confidence: 99%

Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion

Labrador

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The regulators of the Rho-family GTPases, GTPase-activating proteins (GAPs) and guanine exchange factors (GEFs), play important roles in axon guidance. By means of a functional genomic study of the Rho-family GEFs and GAPs in Drosophila, we have identified a Rho-family GAP, CrossGAP (CrGAP), which is involved in Roundabout ( axon guidance ͉ GTPase-activating protein ͉ guanine nucleotide exchange factor ͉ Slit ͉ Roundabout

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“…The SH3 domain of the Abl kinase was selected for comparison as it binds to the same proline-rich CC3 motif of Robo as the srGAP1 SH3 domain (32,33). In the complex of the Abl SH3 domain complex with synthetic peptide 3BP1, the four residues in the tip of the RT loop form a type II ␤-turn in the P3 specificity pocket.…”

Section: Resultsmentioning

confidence: 99%

“…CC2 matches the consensus binding site for the EVH1 domain of the Drosophila Enabled protein and CC3 is a poly-proline stretch (32,39). Abl functions to antagonize Robo signaling, likely through a mechanism involving direct phosphorylation of the Robo receptor on the CC0 and CC1 motifs, but Abl may also bind via its SH3 domain to the CC3 motif in Robo (32,33). Dock can directly bind to the cytoplasmic domain of Robo, but is dependent on the SH3 domains of Dock and the CC2 and CC3 motifs in Robo (38).…”

Section: Discussionmentioning

confidence: 99%

Structural Basis of Robo Proline-rich Motif Recognition by the srGAP1 Src Homology 3 Domain in the Slit-Robo Signaling Pathway

Chen

Liu

et al. 2006

Journal of Biological Chemistry

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The Slit-Robo (sr) GTPase-activating protein (GAPs) are important components in the intracellular pathway mediating Slit-Robo signaling in axon guidance and cell migration. We report the first crystal structure of the srGAP1 SH3 domain at 1.8-Å resolution. The unusual side chain conformation of the conserved Phe-13 in the P1 pocket renders the ligand binding pocket shallow and narrow, which contributes toward the low binding affinity. Moreover, the opposing electrostatic charge and the hydrophobic properties of the P3 specificity pocket are consistent with the observed binding characteristics of the srGAP1 SH3 domain to its ligand. Surface plasmon resonance experiments indicate that the srGAP1 SH3 domain interacts with its natural ligand in a C to N orientation. The srGAP1 SH3 domain can bind to both the CC2 and CC3 motifs in vitro. The N-terminal two acidic residues in the CC3 motif recognition site are necessary for srGAP1 SH3 domain binding. A longer CC3 peptide (CC3-FL) binds with greater affinity than its shorter counterpart, suggesting that the residues surrounding the proline-rich core are important for protein-peptide interactions. Our study reveals previously unknown properties of the srGAP-Robo interaction. Our data provide a structural basis for the srGAP-Robo interaction, consistent with the role of the Robo intracellular domain in interacting with other downstream signaling molecules and mediating versatile and dynamic responses to axon guidance and cell migration cues.

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Abelson tyrosine kinase is required to transduce midline repulsive cues

Cited by 44 publications

References 74 publications

Parallel Genetic and Proteomic Screens Identify Msps as a CLASP–Abl Pathway Interactor in Drosophila

Parallel Genetic and Proteomic Screens Identify Msps as a CLASP–Abl Pathway Interactor in Drosophila

Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion

Structural Basis of Robo Proline-rich Motif Recognition by the srGAP1 Src Homology 3 Domain in the Slit-Robo Signaling Pathway

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