A1 Refereed original research article in a scientific journal
The Orphan Adhesion G Protein-coupled Receptor GPR97 Regulates Migration of Lymphatic Endothelial Cells via the Small GTPases RhoA and Cdc42
Authors: Valtcheva N, Primorac A, Jurisic G, Hollmen M, Detmar M
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Publication year: 2013
Journal: Journal of Biological Chemistry
Journal name in source: JOURNAL OF BIOLOGICAL CHEMISTRY
Journal acronym: J BIOL CHEM
Volume: 288
Issue: 50
First page : 35736
Last page: 35748
Number of pages: 13
ISSN: 0021-9258
DOI: https://doi.org/10.1074/jbc.M113.512954
Abstract
Background: The identification of G protein-coupled receptors (GPCRs) specific for the lymphatic endothelial cells (LECs) is essential for establishing drugs targeting the lymphatic system. Results: GPR97 is an orphan adhesion GPCR that regulates LEC migration. Conclusion: GPR97 is the first known adhesion GPCR involved in lymphatic remodeling. Significance: This first evidence that adhesion GPCRs govern LEC motility opens new possibilities for modulating lymphangiogenesis.The important role of the lymphatic vascular system in pathological conditions such as inflammation and cancer has been increasingly recognized, but its potential as a pharmacological target is poorly exploited. Our study aimed at the identification and molecular characterization of lymphatic-specific G protein-coupled receptors (GPCRs) to assess new targets for pharmacological manipulation of the lymphatic vascular system. We used a TaqMan quantitative RT-PCR-based low density array to determine the GPCR expression profiles of ex vivo isolated intestinal mouse lymphatic (LECs) and blood vascular endothelial cells (BECs). GPR97, an orphan adhesion GPCR of unknown function, was the most highly and specifically expressed GPCR in mouse lymphatic endothelium. Using siRNA silencing, we found that GPR97-deficient primary human LECs displayed increased adhesion and collective cell migration, whereas single cell migration was decreased as compared with nontargeting siRNA-transfected control LECs. Loss of GPR97 shifted the ratio of active Cdc42 and RhoA and initiated cytoskeletal rearrangements, including F-actin redistribution, paxillin and PAK4 phosphorylation, and 1-integrin activation. Our data suggest a possible role of GPR97 in lymphatic remodeling and furthermore provide the first insights into the biological functions of GPR97.
Background: The identification of G protein-coupled receptors (GPCRs) specific for the lymphatic endothelial cells (LECs) is essential for establishing drugs targeting the lymphatic system. Results: GPR97 is an orphan adhesion GPCR that regulates LEC migration. Conclusion: GPR97 is the first known adhesion GPCR involved in lymphatic remodeling. Significance: This first evidence that adhesion GPCRs govern LEC motility opens new possibilities for modulating lymphangiogenesis.The important role of the lymphatic vascular system in pathological conditions such as inflammation and cancer has been increasingly recognized, but its potential as a pharmacological target is poorly exploited. Our study aimed at the identification and molecular characterization of lymphatic-specific G protein-coupled receptors (GPCRs) to assess new targets for pharmacological manipulation of the lymphatic vascular system. We used a TaqMan quantitative RT-PCR-based low density array to determine the GPCR expression profiles of ex vivo isolated intestinal mouse lymphatic (LECs) and blood vascular endothelial cells (BECs). GPR97, an orphan adhesion GPCR of unknown function, was the most highly and specifically expressed GPCR in mouse lymphatic endothelium. Using siRNA silencing, we found that GPR97-deficient primary human LECs displayed increased adhesion and collective cell migration, whereas single cell migration was decreased as compared with nontargeting siRNA-transfected control LECs. Loss of GPR97 shifted the ratio of active Cdc42 and RhoA and initiated cytoskeletal rearrangements, including F-actin redistribution, paxillin and PAK4 phosphorylation, and 1-integrin activation. Our data suggest a possible role of GPR97 in lymphatic remodeling and furthermore provide the first insights into the biological functions of GPR97.
UTU Research Portal