Activation of the repulsive receptor Roundabout inhibits N-cadherin-mediated cell adhesion

Rhee, Jae-Ho; Mahfooz, Najmus; Arregui, Carlos; Lilien, Jack; Balsamo, Janne; VanBerkum, Mark F. A.

doi:10.1038/ncb858

Cited by 174 publications

(154 citation statements)

References 50 publications

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“…For example, reciprocal modulation of growth cone cell adhesion by Msps and CLASP might underlie the two phenotypes we observe in the different mutants. Reduction of adhesion has already been shown to be key in the midline repulsive response to Robo (Rhee et al 2002), whereas an increase in adhesion has long been known to be vital for fasciculation (Rutishauser 1985;Landmesser et al 1988). Interestingly, the Abl kinase that interacts with both Msps and CLASP was also implicated in Robo-dependent modulation of cell adhesion (Rhee et al 2002).…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…It is likely that Slit or Robo receptors have parallel or cooperative roles with cell adhesion systems during heart formation. In vitro, activation of Robo by Slit interferes with N-cadherin-mediated adhesion (25). Future studies will reveal whether Slit and Robos cooperate with homophilic cell adhesion molecules in the developing heart.…”

Section: Discussionmentioning

confidence: 99%

Lateral positioning at the dorsal midline: Slit and Roundabout receptors guide Drosophila heart cell migration

Santiago-Martínez

Soplop

Kramer

2006

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

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Heart morphogenesis requires the coordinated regulation of cell movements and cell-cell interactions between distinct populations of cardiac precursor cells. Little is known about the mechanisms that organize cardiac cells into this complex structure. In this study, we analyzed the role of Slit, an extracellular matrix protein and its transmembrane receptors Roundabout (Robo) and Roundabout2 (Robo2) during morphogenesis of the Drosophila heart tube, a process analogous to early heart formation in vertebrates. During heart assembly, two types of progenitor cells align into rows and coordinately migrate to the dorsal midline of the embryo, where they merge to assemble a linear heart tube. Here we show that cardiac-specific expression of Slit is required to maintain adhesion between cells within each row during dorsal migration. Moreover, differential Robo expression determines the relative distance each row is positioned from the dorsal midline. The innermost CBs express only Robo, whereas the flanking pericardial cells express both receptors. Removal of robo2 causes pericardial cells to shift toward the midline, whereas ectopic robo2 in CBs drives them laterally, resulting in an unfused heart tube. We propose a model in which Slit has a dual role during assembly of the linear heart tube, functioning to regulate both cell positioning and adhesive interactions between migrating cardiac precursor cells.cell adhesion ͉ dorsal vessel ͉ heart morphogenesis

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“…RAFTK and FAK have also been shown to associate with paxillin through their proline-rich C-terminal domains (40). In neuronal cells, Slit has been shown to affect actin cytoskeleton organization through the family of GTPaseactivating proteins and N-cadherins (57,58).…”

Section: Discussionmentioning

confidence: 99%

Slit Protein-mediated Inhibition of CXCR4-induced Chemotactic and Chemoinvasive Signaling Pathways in Breast Cancer Cells

Prasad

Fernandis

Rao

et al. 2004

Journal of Biological Chemistry

117

115

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Slit, which mediates its function by binding to the Roundabout (Robo) receptor, has been shown to regulate neuronal and CXCR4-mediated leukocyte migration. Slit-2 was shown to be frequently inactivated in lung and breast cancers because of hypermethylation of its promoter region. Furthermore, the CXCR4/CXCL12 axis has been reported recently to be actively involved in breast cancer metastasis to target organs such as lymph nodes, lung, and bone. In this study, we sought to characterize the effect of Slit (‫؍‬Slit-2) on the CXCL12/ CXCR4-mediated metastatic properties of breast cancer cells. We demonstrate here that breast cancer cells and tissues derived from breast cancer patients express Robo 1 and 2 receptors. We also show that Slit treatment inhibits CXCL12/CXCR4-induced breast cancer cell chemotaxis, chemoinvasion, and adhesion, the fundamental components that promote metastasis. Slit had no significant effect on the CXCL12-induced internalization process of CXCR4. In addition, characterization of signaling events revealed that Slit inhibits CXCL12-induced tyrosine phosphorylation of focal adhesion components such as RAFTK/Pyk2 at residues 580 and 881, focal adhesion kinase at residue 576, and paxillin. We found that Slit also inhibits CXCL12-induced phosphatidylinositol 3-kinase, p44/42 MAP kinase, and metalloproteinase 2 and 9 activities. However, it showed no effect on JNK and p38 MAP kinase activities. To our knowledge, this is the first report to analyze in detail the effect of Slit on breast cancer cell motility as well as its effect on the critical components of the cancer cell chemotactic machinery. Studies of the Slit-Robo complex may foster new anti-chemotactic approaches to block cancer cell metastasis.

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Activation of the repulsive receptor Roundabout inhibits N-cadherin-mediated cell adhesion

Cited by 174 publications

References 50 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

Lateral positioning at the dorsal midline: Slit and Roundabout receptors guide Drosophila heart cell migration

Slit Protein-mediated Inhibition of CXCR4-induced Chemotactic and Chemoinvasive Signaling Pathways in Breast Cancer Cells

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