Proximity interactome of lymphatic VE-cadherin reveals mechanisms of junctional remodeling and reelin secretion.

Serafin DS, Harris NR, Bálint L, Douglas ES, Caron KM

Nat Commun 2024

1. Nat Commun. 2024 Sep 4;15(1):7734. doi: 10.1038/s41467-024-51918-1. Proximity interactome of lymphatic VE-cadherin reveals mechanisms of junctional remodeling and reelin secretion. Serafin DS(#)(1), Harris NR(#)(1), Bálint L(1), Douglas ES(1), Caron KM(2). Author information: (1)Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, 27599, NC, USA. (2)Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, 111 Mason Farm Road, Chapel Hill, 27599, NC, USA. kathleen_caron@med.unc.edu. (#)Contributed equally The adhesion receptor vascular endothelial (VE)-cadherin transduces an array of signals that modulate crucial lymphatic cell behaviors including permeability and cytoskeletal remodeling. Consequently, VE-cadherin must interact with a multitude of intracellular proteins to exert these functions. Yet, the full protein interactome of VE-cadherin in endothelial cells remains a mystery. Here, we use proximity proteomics to illuminate how the VE-cadherin interactome changes during junctional reorganization from dis-continuous to continuous junctions, triggered by the lymphangiogenic factor adrenomedullin. These analyses identified interactors that reveal roles for ADP ribosylation factor 6 (ARF6) and the exocyst complex in VE-cadherin trafficking and recycling. We also identify a requisite role for VE-cadherin in the in vitro and in vivo control of secretion of reelin-a lymphangiocrine glycoprotein with recently appreciated roles in governing heart development and injury repair. This VE-cadherin protein interactome shines light on mechanisms that control adherens junction remodeling and secretion from lymphatic endothelial cells. © 2024. The Author(s). DOI: 10.1038/s41467-024-51918-1 PMCID: PMC11374903 PMID: 39232006 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interest.

6 Figures Extracted

Fig. 2 PMC

Bioinformatic analysis of the AM-induced VE-cadherin interactome identifies enrichment of secretory and Rho family GTPase pathways. A Gene Ontology (...

Fig. 3 PMC

Comparative analysis of VE-cadherin interactomes identified in whole cell or plasma membrane fractions reveals reproducibly captured proteins and path...

Fig. 4 PMC

Bioinformatic analysis of the plasma membrane-specific AM-induced VE-cadherin interactome identifies a role for secretory vesicles and GTPase activity...

Fig. 5 PMC

AM-mediated VE-cadherin junction remodeling occurs through an endocytic-exocyst pathway. A Proposed model of AM-mediated adherens junction regulation...

Fig. 6 PMC

Inhibition of endocytic-exocyst pathways disrupts VE-cadherin junctional architecture in LECs. A Representative images of VE-cadherin localization in...

Fig. 7 PMC

Lymphatic secretion of reelin requires VE-cadherin plasma membrane junctional organization in vitro and VE-cadherin expression in vivo . A Time cours...