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However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.<\/jats:p>","DOI":"10.1084\/jem.20131706","type":"journal-article","created":{"date-parts":[[2014,8,4]],"date-time":"2014-08-04T20:20:47Z","timestamp":1407183647000},"page":"1741-1758","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":58,"title":["The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation"],"prefix":"10.1084","volume":"211","author":[{"given":"Sachin","family":"Kumar","sequence":"first","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Research Foundation, Cincinnati, OH 45229 1"},{"name":"University of Cincinnati College of Medicine, Cincinnati OH 45229 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juying","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Research Foundation, Cincinnati, OH 45229 1"},{"name":"University of Cincinnati College of Medicine, Cincinnati OH 45229 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupali Sani","family":"Kumar","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Research Foundation, Cincinnati, OH 45229 1"},{"name":"University of Cincinnati College of Medicine, Cincinnati OH 45229 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sribalaji","family":"Lakshmikanthan","sequence":"additional","affiliation":[{"name":"Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53214 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reuben","family":"Kapur","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Cancer Research Institute, Indianapolis, IN 46202 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Kofron","sequence":"additional","affiliation":[{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Research Foundation, Cincinnati, OH 45229 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Chrzanowska-Wodnicka","sequence":"additional","affiliation":[{"name":"Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53214 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Dominique","family":"Filippi","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Cincinnati Children\u2019s Research Foundation, Cincinnati, OH 45229 1"},{"name":"University of Cincinnati College of Medicine, Cincinnati OH 45229 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2014,8,4]]},"reference":[{"key":"2023072602340995400_bib1","doi-asserted-by":"crossref","first-page":"L1137","DOI":"10.1152\/ajplung.2000.279.6.L1137","article-title":"Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury","volume":"279","author":"Abraham","year":"2000","journal-title":"Am. 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