A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress
Hemodynamic forces regulate embryonic organ development, hematopoiesis, vascular remodeling, and atherogenesis. The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and r...
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| Veröffentlicht in: | The Journal of cell biology 2013-06, Vol.201 (6), p.863-873 |
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| container_title | The Journal of cell biology |
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| creator | Liu, Yunhao Collins, Caitlin Kiosses, William B Murray, Ann M Joshi, Monika Shepherd, Tyson R Fuentes, Ernesto J Tzima, Ellie |
| description | Hemodynamic forces regulate embryonic organ development, hematopoiesis, vascular remodeling, and atherogenesis. The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and redox signaling. The activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be modulated by the GTP/GDP state of Rac1; however, the molecular mechanisms of Rac1 activation by flow are poorly understood. Here, we identify a novel polarity complex that directs localized Rac1 activation required for downstream reactive oxygen species (ROS) production. Vav2 is required for Rac1 GTP loading, whereas, surprisingly, Tiam1 functions as an adaptor in a VE-cadherin-p67phox-Par3 polarity complex that directs localized activation of Rac1. Furthermore, loss of Tiam1 led to the disruption of redox signaling both in vitro and in vivo. Our results describe a novel molecular cascade that regulates redox signaling by the coordinated regulation of Rac1 and by linking components of the polarity complex to the NADPH oxidase. |
| doi_str_mv | 10.1083/jcb.201207115 |
| format | Article |
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The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and redox signaling. The activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be modulated by the GTP/GDP state of Rac1; however, the molecular mechanisms of Rac1 activation by flow are poorly understood. Here, we identify a novel polarity complex that directs localized Rac1 activation required for downstream reactive oxygen species (ROS) production. Vav2 is required for Rac1 GTP loading, whereas, surprisingly, Tiam1 functions as an adaptor in a VE-cadherin-p67phox-Par3 polarity complex that directs localized activation of Rac1. Furthermore, loss of Tiam1 led to the disruption of redox signaling both in vitro and in vivo. Our results describe a novel molecular cascade that regulates redox signaling by the coordinated regulation of Rac1 and by linking components of the polarity complex to the NADPH oxidase.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.201207115</identifier><identifier>PMID: 23733346</identifier><identifier>CODEN: JCLBA3</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Animals ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Aorta - physiology ; Blood ; Cadherins - genetics ; Cadherins - metabolism ; Cell Adhesion Molecules - metabolism ; Cell Cycle Proteins - metabolism ; Cells ; Cells, Cultured ; Embryonic Stem Cells - cytology ; Guanine Nucleotide Exchange Factors - genetics ; Guanine Nucleotide Exchange Factors - metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Membrane Proteins - metabolism ; Mice ; Mice, Knockout ; Neuropeptides - genetics ; Neuropeptides - metabolism ; Oxidation-Reduction ; Oxidative Stress - physiology ; Oxygen ; Phosphoproteins - metabolism ; Platelet Endothelial Cell Adhesion Molecule-1 - genetics ; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism ; rac GTP-Binding Proteins - genetics ; rac GTP-Binding Proteins - metabolism ; rac1 GTP-Binding Protein - genetics ; rac1 GTP-Binding Protein - metabolism ; RNA, Small Interfering - genetics ; Shear stress ; Signal Transduction - physiology ; Stress, Mechanical ; T-Lymphoma Invasion and Metastasis-inducing Protein 1</subject><ispartof>The Journal of cell biology, 2013-06, Vol.201 (6), p.863-873</ispartof><rights>Copyright Rockefeller University Press Jun 10, 2013</rights><rights>2013 Liu et al. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c481t-b054342eb7b751bce58a7985404db61c557ee43b15f07597de827bcafc081f313</citedby><cites>FETCH-LOGICAL-c481t-b054342eb7b751bce58a7985404db61c557ee43b15f07597de827bcafc081f313</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23733346$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Yunhao</creatorcontrib><creatorcontrib>Collins, Caitlin</creatorcontrib><creatorcontrib>Kiosses, William B</creatorcontrib><creatorcontrib>Murray, Ann M</creatorcontrib><creatorcontrib>Joshi, Monika</creatorcontrib><creatorcontrib>Shepherd, Tyson R</creatorcontrib><creatorcontrib>Fuentes, Ernesto J</creatorcontrib><creatorcontrib>Tzima, Ellie</creatorcontrib><title>A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>Hemodynamic forces regulate embryonic organ development, hematopoiesis, vascular remodeling, and atherogenesis. The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and redox signaling. The activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be modulated by the GTP/GDP state of Rac1; however, the molecular mechanisms of Rac1 activation by flow are poorly understood. Here, we identify a novel polarity complex that directs localized Rac1 activation required for downstream reactive oxygen species (ROS) production. Vav2 is required for Rac1 GTP loading, whereas, surprisingly, Tiam1 functions as an adaptor in a VE-cadherin-p67phox-Par3 polarity complex that directs localized activation of Rac1. Furthermore, loss of Tiam1 led to the disruption of redox signaling both in vitro and in vivo. Our results describe a novel molecular cascade that regulates redox signaling by the coordinated regulation of Rac1 and by linking components of the polarity complex to the NADPH oxidase.</description><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Aorta - physiology</subject><subject>Blood</subject><subject>Cadherins - genetics</subject><subject>Cadherins - metabolism</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cells</subject><subject>Cells, Cultured</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Guanine Nucleotide Exchange Factors - genetics</subject><subject>Guanine Nucleotide Exchange Factors - metabolism</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Neuropeptides - genetics</subject><subject>Neuropeptides - metabolism</subject><subject>Oxidation-Reduction</subject><subject>Oxidative Stress - physiology</subject><subject>Oxygen</subject><subject>Phosphoproteins - metabolism</subject><subject>Platelet Endothelial Cell Adhesion Molecule-1 - genetics</subject><subject>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</subject><subject>rac GTP-Binding Proteins - genetics</subject><subject>rac GTP-Binding Proteins - metabolism</subject><subject>rac1 GTP-Binding Protein - genetics</subject><subject>rac1 GTP-Binding Protein - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>Shear stress</subject><subject>Signal Transduction - physiology</subject><subject>Stress, Mechanical</subject><subject>T-Lymphoma Invasion and Metastasis-inducing Protein 1</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc2LFDEQxYO4uOPq0asEvHjp3Xx2MhdhWfyChQXRc0jS1TMZepI2SY_Of2_WXQf1VEXVj0e9egi9ouSSEs2vdt5dMkIZUZTKJ2hFpSCdpoI8RStCGO3Wkslz9LyUHSFEKMGfoXPGFedc9CsE1zimA0x4tnX7wx5xaU1IFfZzynaajtj6Gg62QsFfrKfYxgFnGNJPXMIm2inEDQ6xjcqcYgFcEx6nJQy4bMFmXGrblBfobLRTgZeP9QJ9-_D-682n7vbu4-eb69vOC01r54gUXDBwyilJnQeprVrr5kgMrqdeSgUguKNyJEqu1QCaKeft6ImmI6f8Ar170J0Xt4fBQ6zNhJlz2Nt8NMkG8-8mhq3ZpIPhvdK0XzeBt48COX1foFSzD8XDNNkIaSmG8r7XjPWCN_TNf-guLbl95DelGSec9Y3qHiifUykZxtMxlJj7AE0L0JwCbPzrvx2c6D-J8V_pxpfE</recordid><startdate>20130610</startdate><enddate>20130610</enddate><creator>Liu, Yunhao</creator><creator>Collins, Caitlin</creator><creator>Kiosses, William B</creator><creator>Murray, Ann M</creator><creator>Joshi, Monika</creator><creator>Shepherd, Tyson R</creator><creator>Fuentes, Ernesto J</creator><creator>Tzima, Ellie</creator><general>Rockefeller University Press</general><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130610</creationdate><title>A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress</title><author>Liu, Yunhao ; Collins, Caitlin ; Kiosses, William B ; Murray, Ann M ; Joshi, Monika ; Shepherd, Tyson R ; Fuentes, Ernesto J ; Tzima, Ellie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-b054342eb7b751bce58a7985404db61c557ee43b15f07597de827bcafc081f313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Antigens, CD - genetics</topic><topic>Antigens, CD - metabolism</topic><topic>Aorta - physiology</topic><topic>Blood</topic><topic>Cadherins - genetics</topic><topic>Cadherins - metabolism</topic><topic>Cell Adhesion Molecules - metabolism</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cells</topic><topic>Cells, Cultured</topic><topic>Embryonic Stem Cells - cytology</topic><topic>Guanine Nucleotide Exchange Factors - genetics</topic><topic>Guanine Nucleotide Exchange Factors - metabolism</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Neuropeptides - genetics</topic><topic>Neuropeptides - metabolism</topic><topic>Oxidation-Reduction</topic><topic>Oxidative Stress - physiology</topic><topic>Oxygen</topic><topic>Phosphoproteins - metabolism</topic><topic>Platelet Endothelial Cell Adhesion Molecule-1 - genetics</topic><topic>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</topic><topic>rac GTP-Binding Proteins - genetics</topic><topic>rac GTP-Binding Proteins - metabolism</topic><topic>rac1 GTP-Binding Protein - genetics</topic><topic>rac1 GTP-Binding Protein - metabolism</topic><topic>RNA, Small Interfering - genetics</topic><topic>Shear stress</topic><topic>Signal Transduction - physiology</topic><topic>Stress, Mechanical</topic><topic>T-Lymphoma Invasion and Metastasis-inducing Protein 1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Yunhao</creatorcontrib><creatorcontrib>Collins, Caitlin</creatorcontrib><creatorcontrib>Kiosses, William B</creatorcontrib><creatorcontrib>Murray, Ann M</creatorcontrib><creatorcontrib>Joshi, Monika</creatorcontrib><creatorcontrib>Shepherd, Tyson R</creatorcontrib><creatorcontrib>Fuentes, Ernesto J</creatorcontrib><creatorcontrib>Tzima, Ellie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Yunhao</au><au>Collins, Caitlin</au><au>Kiosses, William B</au><au>Murray, Ann M</au><au>Joshi, Monika</au><au>Shepherd, Tyson R</au><au>Fuentes, Ernesto J</au><au>Tzima, Ellie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2013-06-10</date><risdate>2013</risdate><volume>201</volume><issue>6</issue><spage>863</spage><epage>873</epage><pages>863-873</pages><issn>0021-9525</issn><eissn>1540-8140</eissn><coden>JCLBA3</coden><abstract>Hemodynamic forces regulate embryonic organ development, hematopoiesis, vascular remodeling, and atherogenesis. The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and redox signaling. The activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be modulated by the GTP/GDP state of Rac1; however, the molecular mechanisms of Rac1 activation by flow are poorly understood. Here, we identify a novel polarity complex that directs localized Rac1 activation required for downstream reactive oxygen species (ROS) production. Vav2 is required for Rac1 GTP loading, whereas, surprisingly, Tiam1 functions as an adaptor in a VE-cadherin-p67phox-Par3 polarity complex that directs localized activation of Rac1. Furthermore, loss of Tiam1 led to the disruption of redox signaling both in vitro and in vivo. Our results describe a novel molecular cascade that regulates redox signaling by the coordinated regulation of Rac1 and by linking components of the polarity complex to the NADPH oxidase.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>23733346</pmid><doi>10.1083/jcb.201207115</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antigens, CD - genetics Antigens, CD - metabolism Aorta - physiology Blood Cadherins - genetics Cadherins - metabolism Cell Adhesion Molecules - metabolism Cell Cycle Proteins - metabolism Cells Cells, Cultured Embryonic Stem Cells - cytology Guanine Nucleotide Exchange Factors - genetics Guanine Nucleotide Exchange Factors - metabolism Human Umbilical Vein Endothelial Cells Humans Membrane Proteins - metabolism Mice Mice, Knockout Neuropeptides - genetics Neuropeptides - metabolism Oxidation-Reduction Oxidative Stress - physiology Oxygen Phosphoproteins - metabolism Platelet Endothelial Cell Adhesion Molecule-1 - genetics Platelet Endothelial Cell Adhesion Molecule-1 - metabolism rac GTP-Binding Proteins - genetics rac GTP-Binding Proteins - metabolism rac1 GTP-Binding Protein - genetics rac1 GTP-Binding Protein - metabolism RNA, Small Interfering - genetics Shear stress Signal Transduction - physiology Stress, Mechanical T-Lymphoma Invasion and Metastasis-inducing Protein 1 |
| title | A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress |
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