ArticleThe Journal of biological chemistry2011
Phosphatidylinositol-4-phosphate 5-kinase and GEP100/Brag2 protein mediate antiangiogenic signaling by semaphorin 3E-plexin-D1 through Arf6 protein.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 52 citations in OpenAlex.
- Altered cholangiocyte subsets with neural pathway enrichment in metabolic dysfunction-associated steatotic liver disease.Internal and emergency medicine · 2026Article
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- Plexin D1 negatively regulates zebrafish lymphatic development.Development (Cambridge, England) · 2022Article
- IQSEC2-related encephalopathy in males due to missense variants in the pleckstrin homology domain.Clinical genetics · 2022Article
- Insights into the regulatory role of Plexin D1 signalling in cardiovascular development and diseases.Journal of cellular and molecular medicine · 2021Review
- RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells.The EMBO journal · 2020Article
- ARF GTPases and their GEFs and GAPs: concepts and challenges.Molecular biology of the cell · 2019Review
- Article
- CD13 tethers the IQGAP1-ARF6-EFA6 complex to the plasma membrane to promote ARF6 activation, β1 integrin recycling, and cell migration.Science signaling · 2019Article
- Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression.International journal of molecular sciences · 2019Review
- Inhibition of AKT suppresses the initiation and progression ofInternational journal of biological sciences · 2018Article
- Elucidating the role of plexin D1 in body fat distribution and susceptibility to metabolic disease using a zebrafish model system.Adipocyte · 2017Article
- The role of the semaphorins in cancer.Cell adhesion & migration · 2016Review
- The BRAG/IQSec family of Arf GEFs.Small GTPases · 2016Review
- Infantile hemangioma-derived stem cells and endothelial cells are inhibited by class 3 semaphorins.Biochemical and biophysical research communications · 2015Article
- ADP ribosylation factor 6 (ARF6) promotes acrosomal exocytosis by modulating lipid turnover and Rab3A activation.The Journal of biological chemistry · 2015Article
- Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Integrin traffic - the update.Journal of cell science · 2015Review
- The Arf6 GTPase-activating proteins ARAP2 and ACAP1 define distinct endosomal compartments that regulate integrin α5β1 traffic.The Journal of biological chemistry · 2014Article
- Review
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
The semaphorins are a family of secreted or membrane-bound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells. Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADP-ribosylation factor 6), which regulates intracellular trafficking of β1 integrin. However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells. We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrin-mediated focal adhesions and endothelial cell collapse. Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix and migration.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.