期刊
JOURNAL OF CELL BIOLOGY
卷 220, 期 11, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.202006033
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资金
- Fondazione Associazione Italiana per la Ricerca sul Cancro IG grants [13016, 16702, 21315, 19923, 20366, 20119]
- Fondazione Associazione Italiana per la Ricerca sul Cancro under 5 per Mille 2018 grant [21052]
- Fondazione Piemontese per la ricerca sul cancro Onlus Grant MIUR 2010 Vaschetto -5 per mille 2010 MIUR
- Telethon Italy [GGP09175]
- Universita di Torino, Bando Ricerca Locale 2019 [CUP D84I19002940005]
- Associazione Augusto per la Vita
- European Research Council [647057 - rEnDOx]
Dynamic modulation of endothelial cell adhesion and barrier function by the adhesion G protein-coupled receptor Latrophilin 2 (LPHN2) and its ligand FLRT2 plays a crucial role in blood vessel development and functioning.
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.
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