PUBLICATION

GIPC proteins negatively modulate Plexind1 signaling during vascular development

Authors
Carretero-Ortega, J., Chhangawala, Z., Hunt, S., Narvaez, C., Menéndez-González, J., Gay, C.M., Zygmunt, T., Li, X., Torres-Vázquez, J.
ID
ZDB-PUB-190507-27
Date
2019
Source
eLIFE   8: (Journal)
Registered Authors
Carretero-Ortega, Jorge, Chhangawala, Zinal, Gay, Carl Michael, Hunt, Shane, Narvaez, Carlos, Zygmunt, Tomasz
Keywords
GIPC, PlexinD1, Zebrafish, angiogenesis, cell signaling, developmental biology, zebrafish
MeSH Terms
  • Animals
  • Carrier Proteins/metabolism*
  • Endothelial Cells/enzymology*
  • Endothelial Cells/physiology*
  • Neovascularization, Physiologic*
  • Protein Binding
  • Receptors, Cell Surface/metabolism*
  • Semaphorins/metabolism
  • Signal Transduction*
  • Zebrafish
  • Zebrafish Proteins/metabolism*
PubMed
31050647 Full text @ Elife
Abstract
Semaphorins (SEMAs) and their Plexin (PLXN) receptors are central regulators of metazoan cellular communication. SEMA-PLXND1 signaling plays important roles in cardiovascular, nervous, and immune system development, and cancer biology. However, little is known about the molecular mechanisms that modulate SEMA-PLXND1 signaling. As PLXND1 associates with GIPC family endocytic adaptors, we evaluated the requirement for the molecular determinants of their association and PLXND1's vascular role. Zebrafish that endogenously express a Plxnd1 receptor with a predicted impairment in GIPC binding exhibit low penetrance angiogenesis deficits and antiangiogenic drug hypersensitivity. Moreover, gipc mutant fish show angiogenic impairments that are ameliorated by reducing Plxnd1 signaling. Finally, GIPC depletion potentiates SEMA-PLXND1 signaling in cultured endothelial cells. These findings expand the vascular roles of GIPCs beyond those of the Vascular Endothelial Growth Factor (VEGF)-dependent, proangiogenic GIPC1-Neuropilin 1 complex, recasting GIPCs as negative modulators of antiangiogenic PLXND1 signaling and suggest that PLXND1 trafficking shapes vascular development.
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Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
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Errata and Notes