GIPC proteins negatively modulate Plexind1 signaling during vascular development.
Jorge Carretero-Ortega1, Zinal Chhangawala1, Shane Hunt1
1Department of Cell Biology, Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, United States.
Elife
|May 4, 2019
Summary
GIPC proteins negatively regulate Semaphorin-Plexin-D1 (SEMA-PLXND1) signaling, impacting blood vessel development. Modulating this interaction offers new therapeutic strategies for angiogenesis-related conditions.
Area of Science:
- Cellular Biology
- Developmental Biology
- Molecular Biology
Background:
- Semaphorins (SEMAs) and Plexin (PLXN) receptors are crucial for cellular communication and development.
- SEMA-PLXND1 signaling influences cardiovascular, nervous, and immune system development, as well as cancer biology.
- The molecular mechanisms modulating SEMA-PLXND1 signaling are not fully understood.
Purpose of the Study:
- To investigate the role of GIPC family endocytic adaptors in SEMA-PLXND1 signaling.
- To determine the molecular determinants governing the association between PLXND1 and GIPC.
- To elucidate the function of PLXND1 in vascular development.
Main Methods:
- Utilized zebrafish models with genetically modified Plxnd1 receptors and GIPC mutations.
- Assessed angiogenesis deficits and responses to antiangiogenic drugs in zebrafish.
- Investigated SEMA-PLXND1 signaling in cultured endothelial cells following GIPC depletion.
Main Results:
- Zebrafish with impaired GIPC binding to Plxnd1 showed angiogenesis deficits and hypersensitivity to antiangiogenic drugs.
- GIPC mutations led to angiogenic impairments that were rescued by reducing Plxnd1 signaling.
- GIPC depletion enhanced SEMA-PLXND1 signaling in endothelial cells.
Conclusions:
- GIPCs act as negative modulators of antiangiogenic PLXND1 signaling, expanding their known vascular roles.
- PLXND1 trafficking is a key factor shaping vascular development.
- Findings suggest GIPCs are important regulators of angiogenesis beyond the VEGF pathway.
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