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Surprisingly, a significant amount of this protein is internalized in intracellular endosomal-like vesicles where it codistributes with integrin \u03b21. Clustering of \u03b21 integrin leads to JAM-A co-clustering, whereas clustering of JAM-A does not induce integrin association. Neutrophils derived from JAM-A-null mice are unable to correctly internalize \u03b21 integrins upon chemotactic stimuli and this causes impaired uropod retraction and cell motility. Consistently, inhibition of integrin internalization upon treatment with BAPTA-AM induces a comparable phenotype. These data indicate that JAM-A is required for the correct internalization and recycling of integrins during cell migration and might explain why, in its absence, the directional migration of neutrophils towards an inflammatory stimulus is markedly impaired.<\/jats:p>","DOI":"10.1242\/jcs.037127","type":"journal-article","created":{"date-parts":[[2008,12,31]],"date-time":"2008-12-31T18:24:22Z","timestamp":1230747862000},"page":"268-277","source":"Crossref","is-referenced-by-count":81,"title":["JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling"],"prefix":"10.1242","volume":"122","author":[{"given":"Maria Rosaria","family":"Cera","sequence":"first","affiliation":[{"name":"FIRC Institute of Molecular Oncology, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Fabbri","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University and DIBIT San Raffaele Scientific Institute, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Molendini","sequence":"additional","affiliation":[{"name":"FIRC Institute of Molecular Oncology, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Corada","sequence":"additional","affiliation":[{"name":"FIRC Institute of Molecular Oncology, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Orsenigo","sequence":"additional","affiliation":[{"name":"FIRC Institute of Molecular Oncology, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Rehberg","sequence":"additional","affiliation":[{"name":"Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universita\u0308t Mu\u0308nchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph A.","family":"Reichel","sequence":"additional","affiliation":[{"name":"Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universita\u0308t Mu\u0308nchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fritz","family":"Krombach","sequence":"additional","affiliation":[{"name":"Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universita\u0308t Mu\u0308nchen, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruggero","family":"Pardi","sequence":"additional","affiliation":[{"name":"Vita-Salute San Raffaele University and DIBIT San Raffaele Scientific Institute, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Dejana","sequence":"additional","affiliation":[{"name":"FIRC Institute of Molecular Oncology, Milan, Italy"},{"name":"Department of Biomolecular Sciences and Biotechnologies, School of Sciences, University of Milan, Milan, Italy"},{"name":"Mario Negri Institute of Pharmacological Sciences, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042520434688600_REF1","doi-asserted-by":"crossref","unstructured":"Baez, S. 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Increased DC trafficking to lymph nodes and contact hypersensivity in Junctional Adhesion Molecule-A-deficient mouse. J. Clin. Invest.114, 729-738.","DOI":"10.1172\/JCI21231"},{"key":"2021042520434688600_REF8","doi-asserted-by":"crossref","unstructured":"Corada, M., Mariotti, M., Thurston, G., Smith, K., Kunkel, R., Brockhaus, M., Lampugnani, M. G., Martin-Padura, I., Stoppacciaro, A., Ruco, L. et al. (1999). Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo.Proc. Natl. Acad. Sci. USA96, 9815-9820.","DOI":"10.1073\/pnas.96.17.9815"},{"key":"2021042520434688600_REF9","doi-asserted-by":"crossref","unstructured":"Corada, M., Chimenti, S., Cera, M. R., Vinci, M., Salio, M., Fiordaliso, F., De Angelis, N., Villa, A., Bossi, M., Staszewsky, L. I. et al. (2005). Junctional adhesion molecule-A-deficient polymorphonuclear cells show reduced diapedesis in peritonitis and heart ischemia-reperfusion injury. Proc. Natl. Acad. Sci. 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