Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis.
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.
Vanderbilt University School of Medicine, A-4323 MCN, 1161 21st Avenue South, Nashville, TN 37232-2363, USA.
Charlene M
CM
Dunaway
Yoonha
Y
Hwang
Craig W
CW
Lindsley
Rebecca S
RS
Cook
Jane Y
JY
Wu
Mark
M
Boothby
Jin
J
Chen
Dana M
DM
Brantley-Sieders
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D036382:Ephrin-A1 / Q000378:metabolism* / Q000494:pharmacology; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000187:drug effects; D040521:Subcutaneous Tissue / Q000098:blood supply / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D000098552:Slit Homolog 2 Protein
D002352:Carrier Proteins; C504923:Crtc2 protein, mouse; D036382:Ephrin-A1; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015534:Trans-Activators; D014157:Transcription Factors; C525637:rictor protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020744:rac GTP-Binding Proteins; D000098552:Slit Homolog 2 Protein