LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion

J Cell Biol. 2021 Nov 1;220(11):e202006033. doi: 10.1083/jcb.202006033. Epub 2021 Sep 28.


Dynamic modulation of endothelial cell-to-cell and cell-to-extracellular matrix (ECM) adhesion is essential for blood vessel patterning and functioning. Yet the molecular mechanisms involved in this process have not been completely deciphered. We identify the adhesion G protein-coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of endothelial cell (EC) adhesion and barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM contacts, signals through cAMP/Rap1, and inhibits focal adhesion (FA) formation and nuclear localization of YAP/TAZ transcriptional regulators, while promoting tight junction (TJ) assembly. ECs also express an endogenous LPHN2 ligand, fibronectin leucine-rich transmembrane 2 (FLRT2), that prevents ECM-elicited EC behaviors in an LPHN2-dependent manner. Vascular ECs of lphn2a knock-out zebrafish embryos become abnormally stretched, display a hyperactive YAP/TAZ pathway, and lack proper intercellular TJs. Consistently, blood vessels are hyperpermeable, and intravascularly injected cancer cells extravasate more easily in lphn2a null animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Animals, Genetically Modified
  • COS Cells
  • Capillary Permeability / physiology*
  • Cell Adhesion / physiology*
  • Cell Line
  • Cell Nucleus / metabolism
  • Chlorocebus aethiops
  • Endothelium, Vascular / metabolism*
  • Extracellular Matrix / metabolism
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / physiology
  • Trans-Activators / metabolism
  • Zebrafish


  • ADGRL2 protein, human
  • Adaptor Proteins, Signal Transducing
  • Receptors, G-Protein-Coupled
  • Trans-Activators

Associated data

  • figshare/10.6084/m9.figshare.15164292