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

Hu, Hailan; Li, Ming; Labrador, Juan-Pablo; McEwen, Jason M.; Lai, Eric C.; Goodman, Corey S.; Bashaw, Greg J.

doi:10.1073/pnas.0409325102

Cited by 73 publications

(84 citation statements)

References 31 publications

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“…Slit2 also impaired vascular smooth muscle cell migration through suppression of Rac (46). These data are consistent with Slit/Robo-mediated axon repulsion (reviewed in reference 20) through repression of cdc42 and/or Rac GTPases by acti- on May 10, 2018 by guest http://mcb.asm.org/ vation of GTPase activating proteins (GAPs), such as Vilse/ Cross GAP and Slit-Robo GAPs (srGAPs) (22,30,48). Ample evidence also supports a proangiogenic function for Slit2 (reviewed in reference 43), which may be regulated by differential signaling between Robo1 and Robo4 (38,63).…”

Section: Discussionsupporting

confidence: 72%

Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

Dunaway

Hwang

Lindsley

et al. 2011

Molecular and Cellular Biology

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Slit proteins induce cytoskeletal remodeling through interaction with roundabout (Robo) receptors, regulating migration of neurons and nonneuronal cells, including leukocytes, tumor cells, and endothelium. The role of Slit2 in vascular remodeling, however, remains controversial, with reports of both pro-and antiangiogenic activity. We report here that cooperation between Slit2 and ephrin-A1 regulates a balance between the pro-and antiangiogenic functions of Slit2. While Slit2 promotes angiogenesis in culture and in vivo as a single agent, Slit2 potently inhibits angiogenic remodeling in the presence of ephrin-A1. Slit2 stimulates angiogenesis through mTORC2-dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of ephrin-A1. Activated Rac or Akt partially rescues vascular assembly and motility in costimulated endothelium. Taken together, these data suggest that Slit2 differentially regulates angiogenesis in the context of ephrin-A1, providing a plausible mechanism for the pro-versus antiangiogenic functions of Slit2. Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms. Angiogenesis, the process by which new blood vessels sprout from preexisting vessels, is critical for proper embryonic development and normal tissue homeostasis and contributes to the pathogenesis of many diseases, including cancer. Proper vessel morphogenesis requires a balance between angiogenic stimuli, which regulate endothelial cell invasion and migration, proliferation, and tubulogenesis, and angiostatic factors that terminate or inhibit these processes upon vessel maturation to promote vascular stability (reviewed in references 13, 14, 24, and 58). Members of the Slit/roundabout (Robo) gene family have recently emerged as key regulators of vascular remodeling and homeostasis, particularly with the discovery of an endothelial cell-specific Robo receptor, Robo4/Magic roundabout (reviewed in reference 43).The three Slit proteins (Slit1-3) identified in vertebrates interact with receptors of the Robo family (Robo1-4), Robo1 and Robo4 being most highly expressed in endothelial cells (76). While Robo receptors lack intrinsic kinase activity, the intracellular portions of the receptors contain several conserved CC motifs that can interact with intracellular kinases, such as Abelson kinase (Abl) and its substrate enabled (Ena), as well as GTPase activating proteins (GAPs) that modulate the activities of Rho family GTPases. These interactions link Slit-Robo signaling to cytoskeletal remodeling, which promotes chemotaxis or chemorepulsion downstream of Robo signaling, depending upon the cell type and physiologic context (reviewed in references 28 and 43). Identified originally in Drosophila melanogaster (reviewed in reference 20) and later in vertebrates (12, 47), the role of Slit proteins in regulation of angiogenesis is controversial, with reports of both proangiogenic (37, 38, 63, 69, 75) and antiangiogenic (26, 34, 35, 46, 55) activity....

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Section: Discussionsupporting

confidence: 72%

Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

Dunaway

Hwang

Lindsley

et al. 2011

Molecular and Cellular Biology

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“…Furthermore, other members of the robo family (namely, robo1 and robo2) do not rescue robo4 knockdown phenotypes, suggesting vascular-specific function for robo4. Recently, similar results in which overexpression and knockdown experiments show identical phenotype have been reported for vilse, a GTPase-activating protein that links the robo signaling to rac in regulating midline axonal repulsion (32,33), suggesting that for robo in general, too much or too little leads to defects in signaling outputs.…”

Section: Discussionsupporting

confidence: 56%

roundabout4 is essential for angiogenesis in vivo

Bedell

Yeo

Park

et al. 2005

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

199

189

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Stereotypical patterns of vascular and neuronal networks suggest that specific genetic programs tightly control path determination and, consequently, angiogenesis and axon-guidance mechanisms. Our study focuses on one member of the roundabout family of receptors, which traditionally mediate repulsion from the midline. Here, we characterize a fourth member of this family, roundabout4 (robo4), which is the predominant roundabout (robo) that is expressed in embryonic zebrafish vasculature. Gene knockdown and overexpression approaches show that robo4 is essential for coordinated symmetric and directed sprouting of intersomitic vessels and provide mechanistic insights into this process. Also, human robo4 gene functionally compensates for loss of robo4 gene function, suggesting evolutionary conservation. This article reports an endothelial-specific function for a robo gene in vertebrates in vivo.axon guidance ͉ endothelial cell ͉ zebrafish V ascular and neural networks established by angiogenesis and neurogenesis are essential for the regulation of physiological processes. Whether the processes of blood-vessel and peripheralnerve formation are intimately associated at a mechanistic level is a subject of active investigation (1). Recently, description of cellsurface molecules that are shared by neuronal and endothelial cells has suggested that this association may be more prevalent than previously thought. Neuropilin (2), ephrin (3), and plexin (4) are a few examples of molecules that are implicated in both processes. Recently, roundabout (robo), a class of neural guidance receptors that bind slit ligands have joined this group (5). slit-robo signaling mediates axonal repulsion (6) and inhibition of leukocyte migration (7). In vertebrate systems, three robo receptor family members were identified, all with prominent neural expression (8, 9). More recently, a fourth member of the robo gene family, roundabout4 (robo4) was identified (10). Compared with the canonical robo structure, robo4 is smaller in that it possesses only two of the five Ig and two of the three fibronectin domains present in the extracellular component of robo1, robo2, and robo3 (11). robo4 has been described as endothelial-specific, and it binds to slit and inhibits the migration of heterologous cells that express robo4 and primary endothelial cells (12). Although studies of robo4 in endothelial cells suggest that robo signaling is important for regulating endothelial cell migration, there are no reports that document the role of robo signaling in vascular development in vivo. Here, we cloned a zebrafish (Danio rerio) ortholog of human robo4 (hrobo4) and studied its expression and role in vascular development by gene knockdown and overexpression approaches. In contrast to the endothelial-specific expression of murine robo4, zebrafish robo4 is expressed in both endothelial and neural tissues with vascular expression seen in angioblasts, the dorsal aorta (DA), the posterior cardinal vein, and intersomitic vessels (ISV). Morpholino (MO) knockdown of robo...

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“…Small GTPases mediate osteoclastogenesis, including osteoclast fusion (26,27), and the SLIT/ROBO system is one of their critical regulators (28). We thus assessed the effect of SLIT3 on Table 1 We were unable to directly assess the effects of a Robo2 or Robo3 deletion in mice due to embryonic lethality (30,31), and we therefore assessed the bone phenotypes of Robo1 -/-mice (Supplemental Figure 6E).…”

Section: Slit3 Stimulates the Migration And Proliferation Of Osteoblamentioning

confidence: 99%

Osteoclast-secreted SLIT3 coordinates bone resorption and formation

Kim

Lee

et al. 2018

Journal of Clinical Investigation

128

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

Cited by 73 publications

References 31 publications

Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

Cooperative Signaling between Slit2 and Ephrin-A1 Regulates a Balance between Angiogenesis and Angiostasis

roundabout4 is essential for angiogenesis in vivo

Osteoclast-secreted SLIT3 coordinates bone resorption and formation

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