Rebecca Cook
Faculty Member
Last active: 4/15/2019

Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis.

Dunaway CM, Hwang Y, Lindsley CW, Cook RS, Wu JY, Boothby M, Chen J, Brantley-Sieders DM
Mol Cell Biol. 2011 31 (3): 404-16

PMID: 21135133 · PMCID: PMC3028625 · DOI:10.1128/MCB.00667-10

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.

MeSH Terms (21)

Animals Carrier Proteins Cattle Cell Movement Endothelial Cells Enzyme Activation Ephrin-A1 Genes, Dominant HEK293 Cells Humans Intercellular Signaling Peptides and Proteins Mice Neovascularization, Physiologic Nerve Tissue Proteins Proto-Oncogene Proteins c-akt rac GTP-Binding Proteins Rapamycin-Insensitive Companion of mTOR Protein Signal Transduction Subcutaneous Tissue Trans-Activators Transcription Factors

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