The G protein betagamma subunit mediates reannealing of adherens junctions to reverse endothelial permeability increase by thrombin.

The Journal of Experimental Medicine
Nebojsa KnezevicDolly Mehta

Abstract

The inflammatory mediator thrombin proteolytically activates protease-activated receptor (PAR1) eliciting a transient, but reversible increase in vascular permeability. PAR1-induced dissociation of Galpha subunit from heterotrimeric Gq and G12/G13 proteins is known to signal the increase in endothelial permeability. However, the role of released Gbetagamma is unknown. We now show that impairment of Gbetagamma function does not affect the permeability increase induced by PAR1, but prevents reannealing of adherens junctions (AJ), thereby persistently elevating endothelial permeability. We observed that in the naive endothelium Gbeta1, the predominant Gbeta isoform is sequestered by receptor for activated C kinase 1 (RACK1). Thrombin induced dissociation of Gbeta1 from RACK1, resulting in Gbeta1 interaction with Fyn and focal adhesion kinase (FAK) required for FAK activation. RACK1 depletion triggered Gbeta1 activation of FAK and endothelial barrier recovery, whereas Fyn knockdown interrupted with Gbeta1-induced barrier recovery indicating RACK1 negatively regulates Gbeta1-Fyn signaling. Activated FAK associated with AJ and stimulated AJ reassembly in a Fyn-dependent manner. Fyn deletion prevented FAK activation and augmented lung...Continue Reading

References

Sep 18, 1992·Cell·W J Tang, A G Gilman
Feb 1, 1994·Proceedings of the National Academy of Sciences of the United States of America·D RonD Mochly-Rosen
Mar 21, 1996·Nature·S HerlitzeW A Catterall
Jan 15, 1997·The Journal of Clinical Investigation·M H DraznerR J Lefkowitz
Jan 1, 1997·Annual Review of Pharmacology and Toxicology·D E Clapham, E J Neer
Feb 7, 1998·Proceedings of the National Academy of Sciences of the United States of America·E R Neptune, H R Bourne
Jan 1, 1997·Annual Review of Cell and Developmental Biology·S M Thomas, J S Brugge
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·S R Coughlin
Dec 14, 1999·The Journal of Biological Chemistry·S RouraM Duñach
May 20, 2000·DNA Research : an International Journal for Rapid Publication of Reports on Genes and Genomes·E H HurowitzH Shizuya
Mar 30, 2001·The Journal of Biological Chemistry·T MourtonS M Brady-Kalnay
Apr 21, 2001·Oncogene·W F Schwindinger, J D Robishaw
Jul 31, 2001·Biochimica Et Biophysica Acta·M D Schaller
Sep 25, 2001·Journal of Applied Physiology·S M Dudek, J G Garcia
Apr 12, 2002·Proceedings of the National Academy of Sciences of the United States of America·Rami YakaDorit Ron
Oct 3, 2002·The Journal of Biological Chemistry·Edward J DellHeidi E Hamm
Mar 22, 2003·The Journal of Biological Chemistry·Farida GoubaevaAlan V Smrcka
May 16, 2003·Vascular Pharmacology·Chinnaswamy TiruppathiAsrar B Malik
May 16, 2003·Vascular Pharmacology·Sarah Y Yuan
May 20, 2003·The Journal of Biological Chemistry·Michael HolinstatAsrar B Malik
Dec 6, 2003·Circulation Research·Panos KouklisAsrar B Malik
Dec 13, 2003·Endocrine Reviews·Theresa M Cabrera-VeraHeidi E Hamm
Dec 16, 2003·American Journal of Physiology. Lung Cellular and Molecular Physiology·Seema IyerPeter A Vincent
Feb 14, 2004·The Journal of Biological Chemistry·Songhai ChenHeidi E Hamm
Mar 17, 2004·American Journal of Respiratory and Critical Care Medicine·Xinqi PengJoe G N Garcia
Apr 13, 2004·Molecular Biology of the Cell·Celeste M NelsonChristopher S Chen
Jun 16, 2004·Current Opinion in Cell Biology·Janet D Robishaw, Catherine H Berlot
Jul 28, 2004·Journal of Molecular and Cellular Cardiology·Songhai ChenHeidi E Hamm
Aug 12, 2004·Molecular Interventions·Miller B JonesShelley B Hooks

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Citations

Jun 10, 2010·Transplantation·Thet Su Win, Gavin J Pettigrew
Sep 18, 2012·American Journal of Physiology. Lung Cellular and Molecular Physiology·Havovi ChichgerElizabeth O Harrington
Dec 20, 2011·American Journal of Respiratory Cell and Molecular Biology·Katie L GrinnellElizabeth O Harrington
Jan 12, 2013·Cell Communication and Signaling : CCS·Anita BoratkóCsilla Csortos
Jan 23, 2015·Pulmonary Circulation·Sukriti SukritiDolly Mehta
May 10, 2011·Microvascular Research·Katie L Grinnell, Elizabeth O Harrington
Feb 8, 2013·Thrombosis and Haemostasis·Lauren M Goddard, M Luisa Iruela-Arispe
Aug 1, 2014·Thrombosis and Haemostasis·B Marcos-RamiroJ Millán
Oct 12, 2012·Thrombosis and Haemostasis·Annette von DrygalskiJohn H Griffin
Oct 16, 2014·American Journal of Respiratory Cell and Molecular Biology·Havovi ChichgerElizabeth O Harrington
May 4, 2016·The Journal of Cell Biology·Beatriz Marcos-RamiroJaime Millán
Nov 12, 2015·Mediators of Inflammation·Alejandro Pablo Adam
Jan 20, 2018·American Journal of Physiology. Lung Cellular and Molecular Physiology·Qing LuSharon Rounds
Dec 15, 2015·Arteriosclerosis, Thrombosis, and Vascular Biology·Zhibo YanGuochang Hu
Jan 9, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Charu RajputDolly Mehta
May 30, 2019·Physiological Reviews·Nina WettschureckStefan Offermanns
Mar 26, 2019·American Journal of Physiology. Lung Cellular and Molecular Physiology·Karthik SureshMahendra Damarla
Apr 23, 2013·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·Kimberly M ArnoldRobert B Wysolmerski
Feb 14, 2014·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·Zhe SunGerald A Meininger
Nov 9, 2014·American Journal of Physiology. Lung Cellular and Molecular Physiology·Dolly MehtaWolfgang M Kuebler
Nov 19, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Havovi ChichgerElizabeth O Harrington
May 17, 2015·The Journal of Biological Chemistry·Petros AndrikopoulosMuhammad M Yaqoob
Jul 15, 2015·American Journal of Physiology. Lung Cellular and Molecular Physiology·Kathirvel KandasamyKaushik Parthasarathi
Dec 4, 2016·American Journal of Physiology. Lung Cellular and Molecular Physiology·Karthik SureshLarissa A Shimoda
Sep 1, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Mohammad TauseefDolly Mehta
Feb 22, 2017·Scientific Reports·Pascal YazbeckDolly Mehta
Jun 19, 2013·American Journal of Physiology. Lung Cellular and Molecular Physiology·Tracy Thennes SchmidtDolly Mehta
Oct 11, 2011·American Journal of Physiology. Lung Cellular and Molecular Physiology·Qing LuSharon Rounds
Aug 11, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nityanand SrivastavaDolly Mehta
Oct 19, 2020·The American Journal of Pathology·Colin E EvansYou-Yang Zhao
Mar 30, 2010·Thrombosis Research·Keren BorensztajnC Arnold Spek

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Methods Mentioned

BETA
coimmunoprecipitation
transfection
electrophoresis

Software Mentioned

MetaMorph

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