LPHN2 Inhibits Vascular Permeability by Differential Control of Endothelial Cell Adhesion

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2021 Sep 28

PMID 34581723

Citations 13

Authors

Chiara Camillo

Nicola Facchinello

Giulia Villari

Giulia Mana

Noemi Gioelli

Chiara Sandri

Matteo Astone

Dora Tortarolo

Fabiana Clapero

Dafne Gays

Roxana E Oberkersch

Marco Arese

Luca Tamagnone

Donatella Valdembri

Massimo M Santoro

Guido Serini

Affiliations

Soon will be listed here.

Abstract

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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References

Lilja J, Zacharchenko T, Georgiadou M, Jacquemet G, De Franceschi N, Peuhu E . SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. Nat Cell Biol. 2017; 19(4):292-305. PMC: 5386136. DOI: 10.1038/ncb3487. View

Langenhan T, Aust G, Hamann J . Sticky signaling--adhesion class G protein-coupled receptors take the stage. Sci Signal. 2013; 6(276):re3. DOI: 10.1126/scisignal.2003825. View

Lee S, Stanton A, Tong X, Yang F . Hydrogels with enhanced protein conjugation efficiency reveal stiffness-induced YAP localization in stem cells depends on biochemical cues. Biomaterials. 2019; 202:26-34. PMC: 6447317. DOI: 10.1016/j.biomaterials.2019.02.021. View

Camillo C, Gioelli N, Bussolino F, Serini G . An Electrical Impedance-Based Method for Quantitative Real-Time Analysis of Semaphorin-Elicited Endothelial Cell Collapse. Methods Mol Biol. 2016; 1493:195-207. DOI: 10.1007/978-1-4939-6448-2_14. View

Seiradake E, Jones E, Klein R . Structural Perspectives on Axon Guidance. Annu Rev Cell Dev Biol. 2016; 32:577-608. DOI: 10.1146/annurev-cellbio-111315-125008. View

Jaffe E, Nachman R, Becker C, Minick C . Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973; 52(11):2745-56. PMC: 302542. DOI: 10.1172/JCI107470. View

Lyle K, Raaijmakers J, Bruinsma W, Bos J, de Rooij J . cAMP-induced Epac-Rap activation inhibits epithelial cell migration by modulating focal adhesion and leading edge dynamics. Cell Signal. 2008; 20(6):1104-16. DOI: 10.1016/j.cellsig.2008.01.018. View

Zancan I, Bellesso S, Costa R, Salvalaio M, Stroppiano M, Hammond C . Glucocerebrosidase deficiency in zebrafish affects primary bone ossification through increased oxidative stress and reduced Wnt/β-catenin signaling. Hum Mol Genet. 2014; 24(5):1280-94. DOI: 10.1093/hmg/ddu538. View

Lagarrigue F, Kim C, Ginsberg M . The Rap1-RIAM-talin axis of integrin activation and blood cell function. Blood. 2016; 128(4):479-87. PMC: 4965904. DOI: 10.1182/blood-2015-12-638700. View

10.

Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F . Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature. 2003; 424(6947):391-7. DOI: 10.1038/nature01784. View

11.

Wang Y, He H, Srivastava N, Vikarunnessa S, Chen Y, Jiang J . Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Sci Signal. 2012; 5(207):ra6. PMC: 3413289. DOI: 10.1126/scisignal.2002636. View

12.

Galie P, van Oosten A, Chen C, Janmey P . Application of multiple levels of fluid shear stress to endothelial cells plated on polyacrylamide gels. Lab Chip. 2015; 15(4):1205-12. PMC: 4500630. DOI: 10.1039/c4lc01236d. View

13.

Choi H, Zhang H, Park H, Choi K, Lee H, Agrawal V . Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat Commun. 2015; 6:6943. DOI: 10.1038/ncomms7943. View

14.

Kim J, Kim Y, Kim J, Park D, Bae H, Lee D . YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Invest. 2017; 127(9):3441-3461. PMC: 5669570. DOI: 10.1172/JCI93825. View

15.

Follain G, Osmani N, Azevedo A, Allio G, Mercier L, Karreman M . Hemodynamic Forces Tune the Arrest, Adhesion, and Extravasation of Circulating Tumor Cells. Dev Cell. 2018; 45(1):33-52.e12. DOI: 10.1016/j.devcel.2018.02.015. View

16.

Sasaki K, Kojitani N, Hirose H, Yoshihama Y, Suzuki H, Shimada M . Shank2 Binds to aPKC and Controls Tight Junction Formation with Rap1 Signaling during Establishment of Epithelial Cell Polarity. Cell Rep. 2020; 31(1):107407. DOI: 10.1016/j.celrep.2020.02.088. View

17.

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

18.

Worzfeld T, Offermanns S . Semaphorins and plexins as therapeutic targets. Nat Rev Drug Discov. 2014; 13(8):603-21. DOI: 10.1038/nrd4337. View

19.

Christensen A, Selheim F, de Rooij J, Dremier S, Schwede F, Dao K . cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension. J Biol Chem. 2003; 278(37):35394-402. DOI: 10.1074/jbc.M302179200. View

20.

Ollion J, Cochennec J, Loll F, Escude C, Boudier T . TANGO: a generic tool for high-throughput 3D image analysis for studying nuclear organization. Bioinformatics. 2013; 29(14):1840-1. PMC: 3702251. DOI: 10.1093/bioinformatics/btt276. View