Heparan Sulfate Proteoglycan Syndecan Promotes Axonal and Myotube Guidance by Slit/Robo Signaling

Steigemann, Patrick; Molitor, Andreas; Fellert, Sonja; Jäckle, Herbert; Vorbrüggen, Gerd

doi:10.1016/j.cub.2004.01.006

Cited by 178 publications

(123 citation statements)

References 24 publications

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“…These experiments did not reveal which HSPGs are critical for Slit-Robo signalling, however. A first clue came from the observation that the expression patterns of Robo and the HSPG syndecan overlap in the Drosophila nervous system [22,23]. Genetic experiments in Drosophila and C. elegans indeed demonstrated that syndecan has to be present on the same axon as Robo for Slit-Robo signalling to occur normally [22][23][24].…”

Section: Slit-hs Interactionsmentioning

confidence: 98%

“…To add further complexity, Robos also appear to have a Slit-independent function in homophilic cell adhesion [21]. Finally, the HSPG [HS (heparan sulphate) proteoglycan] syndecan was recently identified as a coreceptor for Slit [22][23][24]. While the importance of Slit-Robo signalling for many biological processes is well established, our understanding of the molecular mechanisms involved is limited.…”

Section: Introductionmentioning

confidence: 96%

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Interaction of the guidance molecule Slit with cellular receptors

Hohenester

Hussain

Howitt

2006

Biochemical Society Transactions

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Slits are large secreted glycoproteins characterized by an unusual tandem of four LRR (leucine-rich repeat) domains in their N-terminal half. Slit proteins were initially described as repulsive guidance cues in neural development, but it has become clear that they have additional important functions, for instance in the vasculature and immune system. Genetic studies have identified two types of cellular receptors for Slits: Robos (Roundabout) and the HS (heparan sulphate) proteoglycan syndecan. The intracellular signalling cascade downstream of Robo activation is slowly being elucidated, but the mechanism of transmembrane signalling by Robo has remained obscure. No active signalling role for syndecan has yet been demonstrated. Slit-HS interactions may be important for shaping the presumed Slit gradient or presenting Slit at its target cell surface. Recent studies have mapped the binding sites for Robos and HS/heparin to discrete Slit domains. Robos bind to the second LRR domain of Slit, whereas HS/heparin binds with very high affinity to the C-terminal portion of Slit. Slit activity is likely to be modulated by physiological proteolytic cleavage in the region separating the Robo and HS/heparin-binding sites.

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Section: Slit-hs Interactionsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 96%

Interaction of the guidance molecule Slit with cellular receptors

Hohenester

Hussain

Howitt

2006

Biochemical Society Transactions

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“…Each family member has a unique extracellular domain sequence, but all This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E04 -10 -0907) on June 1, 2005. contain sites for addition of glycosaminoglycan (GAG) chains proximal to the amino-terminus (reviewed by Rapraeger and Ott, 1998;Bernfield et al, 1999). Many functions of syndecans result from their activities as coreceptors through the binding of growth factors to the GAG chains (for example, Johnson et al, 2004;Steigemann et al, 2004). The transmembrane domains are highly conserved and the short cytoplasmic domains contain two conserved regions, C1 and C2, that have the same sequence in all syndecan family members.…”

Section: Introductionmentioning

confidence: 99%

Functional Role of Syndecan-1 Cytoplasmic V Region in Lamellipodial Spreading, Actin Bundling, and Cell Migration

Chakravarti

Sapountzi

Adams

2005

MBoC

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Cell protrusions contribute to cell motility and migration by mediating the outward extension and initial adhesion of cell edges. In many cells, these extensions are supported by actin bundles assembled by the actin cross-linking protein, fascin. Multiple extracellular cues regulate fascin and here we focus on the mechanism by which the transmembrane proteoglycan, syndecan-1, specifically activates lamellipodial cell spreading and fascin-and-actin bundling when clustered either by thrombospondin-1, laminin, or antibody to the syndecan-1 extracellular domain. There is almost no knowledge of the signaling mechanisms of syndecan-1 cytoplasmic domain and we have tested the hypothesis that the unique V region of syndecan-1 cytoplasmic domain has a crucial role in these processes. By four criteria-the activities of N-cadherin/V region chimeras, syndecan-1 deletion mutants, or syndecan-1 point mutants, and specific inhibition by a membranepermeable TAT-V peptide-we demonstrate that the V region is necessary and sufficient for these cell behaviors and map the molecular basis for its activity to multiple residues located across the V region. These activities correlate with a V-region-dependent incorporation of cell-surface syndecan-1 into a detergent-insoluble form. We also demonstrate functional roles of syndecan-1 V region in laminin-dependent C2C12 cell adhesion and three-dimensional cell migration. These data identify for the first time specific cell behaviors that depend on signaling through the V region of syndecan-1.

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“…Of note is that all Robo receptors except for Robo4 contain the Ig domain, which binds to Slit2 [33]. Thus, it is possible that a co-receptor, such as Robo1, syndecans [36], or heparan sulfate [37], is required for Slit2/Robo4 interaction. A recent genetic study has clearly shown that Slit2 is involved in Robo4-mediated downregulation of VEGF angiogenesis in breast [38].…”

Section: Discussionmentioning

confidence: 96%

The differential roles of Slit2-exon 15 splicing variants in angiogenesis and HUVEC permeability

et al. 2015

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Slit2, a secreted glycoprotein, is down-regulated in many cancers. Slit2/Robo signaling pathway plays an important, but controversial, role in angiogenesis. We identified splicing variants of Slit2 at exon 15, Slit2-WT and Slit2-ΔE15, with differential effects on proliferation and invasive capability of lung cancer cells. The aim of this study was to elucidate the differential roles of these exon 15 splicing variants in angiogenesis. Our results revealed that both Slit2-WT and Slit2-ΔE15 inhibit motility of human umbilical vein endothelial cells (HUVECs). The conditioned medium (CM) collected from CL1-5/VC or CL1-5/Slit2-WT lung adenocarcinoma cells blocked HUVEC tube formation and angiogenesis on chorioallantoic membrane (CAM) assay when compared with untreated HUVECs and CAM, respectively. However, CM of CL1-5/Slit2-ΔE15 restored the quality of tubes and the size of vessels. Although both Slit2-WT and Slit2-ΔE15 inhibited permeability induced by CM of cancer cells, Slit2-ΔE15 exhibited stronger effect. These results suggested that Slit2-ΔE15 plays important roles in normalization of blood vessels by enhancing tube quality and tightening endothelial cells, while Slit2-WT only enhances tightening of endothelial cells. It appears that Robo4 is responsible for Slit2 isoform-mediated inhibition of permeability, while neither Robo1 nor Robo4 is required for Slit2-ΔE15-enhanced tube quality. The results of this study suggest that Slit2-ΔE15 splicing form is a promising molecule for normalizing blood vessels around a tumor, which, in turn, may increase efficacy of chemotherapy and radiotherapy.

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Heparan Sulfate Proteoglycan Syndecan Promotes Axonal and Myotube Guidance by Slit/Robo Signaling

Cited by 178 publications

References 24 publications

Interaction of the guidance molecule Slit with cellular receptors

Interaction of the guidance molecule Slit with cellular receptors

Functional Role of Syndecan-1 Cytoplasmic V Region in Lamellipodial Spreading, Actin Bundling, and Cell Migration

The differential roles of Slit2-exon 15 splicing variants in angiogenesis and HUVEC permeability

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