Sci signal
| Autor: | Vincent Jecko, Thomas Wavasseur, Thierry Couffinhal, Etienne Roux, Raj Nayan Sewduth, Pascale Dufourcq, Héléna Kovacic, Cécile Duplàa, Sylvie Jeaningros, Nicolas Fritsch, Béatrice Jaspard-Vinassa, Mathieu Pernot |
|---|---|
| Přispěvatelé: | Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Endothelial Cells/cytology/*metabolism Vascular permeability Cell Cycle Proteins Inbred C57BL Biochemistry Cell junction Mice Edema Wnt Signaling Pathway Cells Cultured Protein Kinase C Actin Cytoskeleton/metabolism Mice Knockout Cultured biology Ubiquitin-Protein Ligases/genetics/*metabolism Article RECHERCHE Brain Infarction Middle Cerebral Artery Intercellular Junctions Ubiquitin ligase Cell biology Vascular endothelial growth factor B Endothelial stem cell Stroke Actin Cytoskeleton Middle Cerebral Artery/complications/genetics/metabolism Carrier Proteins/genetics/metabolism Embryo Infarction Circulatory system Signal transduction medicine.symptom Cells Knockout Ubiquitin-Protein Ligases Stroke/etiology/genetics/metabolism Capillary Permeability 03 medical and health sciences Cell Adhesion Molecules/genetics/metabolism Mammalian/blood supply/embryology/metabolism medicine Animals Humans Wnt Signaling Pathway/genetics Molecular Biology Adaptor Proteins Signal Transducing Animal Brain/blood supply/embryology/metabolism Endothelial Cells Membrane Proteins Cell Biology Embryo Mammalian Mice Inbred C57BL Disease Models Animal 030104 developmental biology Disease Models Protein Kinase C/genetics/*metabolism biology.protein Carrier Proteins Cell Adhesion Molecules [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Science Signaling Science Signaling, American Association for the Advancement of Science, In press, 10, pp.eaag3209. ⟨10.1126/scisignal.aag3209⟩ |
| ISSN: | 1937-9145 |
| DOI: | 10.1126/scisignal.aag3209⟩ |
| Popis: | Endothelial cells serve as a barrier between blood and tissues. Maintenance of the endothelial cell barrier depends on the integrity of intercellular junctions, which is regulated by a polarity complex that includes the ζ isoform of atypical protein kinase C (PKCζ) and partitioning defective 3 (PAR3). We revealed that the E3 ubiquitin ligase PDZ domain-containing ring finger 3 (PDZRN3) regulated endothelial intercellular junction integrity. Endothelial cell-specific overexpression of Pdzrn3 led to early embryonic lethality with severe hemorrhaging and altered organization of endothelial intercellular junctions. Conversely, endothelial-specific loss of Pdzrn3 prevented vascular leakage in a mouse model of transient ischemic stroke, an effect that was mimicked by pharmacological inhibition of PKCζ. PDZRN3 regulated Wnt signaling and associated with a complex containing PAR3, PKCζ, and the multi-PDZ domain protein MUPP1 (Discs Lost-multi-PDZ domain protein 1) and targeted MUPP1 for proteasomal degradation in transfected cells. Transient ischemic stroke increased the ubiquitination of MUPP1, and deficiency of MUPP1 in endothelial cells was associated with decreased localization of PKCζ and PAR3 at intercellular junctions. In endothelial cells, Pdzrn3 overexpression increased permeability through a PKCζ-dependent pathway. In contrast, Pdzrn3 depletion enhanced PKCζ accumulation at cell-cell contacts and reinforced the cortical actin cytoskeleton under stress conditions. These findings reveal how PDZRN3 regulates vascular permeability through a PKCζ-containing complex. |
| Databáze: | OpenAIRE |
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