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First published online December 31, 2008
doi: 10.1242/10.1242/jcs.037127

Journal of Cell Science 122, 268-277 (2009)
Published by The Company of Biologists 2009
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Research Article

JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling

Maria Rosaria Cera1, Monica Fabbri2, Cinzia Molendini1, Monica Corada1, Fabrizio Orsenigo1, Markus Rehberg3, Christoph A. Reichel3, Fritz Krombach3, Ruggero Pardi2 and Elisabetta Dejana1,4,5,*

1 FIRC Institute of Molecular Oncology, Milan, Italy
2 Vita-Salute San Raffaele University and DIBIT San Raffaele Scientific Institute, Milan, Italy
3 Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
4 Department of Biomolecular Sciences and Biotechnologies, School of Sciences, University of Milan, Milan, Italy
5 Mario Negri Institute of Pharmacological Sciences, Milan, Italy

* Author for correspondence (e-mail: elisabetta.dejana{at}ifom-ieo-campus.it)

Accepted 24 October 2008

The membrane-associated adhesion molecule JAM-A is required for neutrophil infiltration in inflammatory or ischemic tissues. JAM-A expressed in both endothelial cells and neutrophils has such a role, but the mechanism of action remains elusive. Here we show that JAM-A has a cell-autonomous role in neutrophil chemotaxis both in vivo and in vitro, which is independent of the interaction of neutrophils with endothelial cells. On activated neutrophils, JAM-A concentrates in a polarized fashion at the leading edge and uropod. Surprisingly, a significant amount of this protein is internalized in intracellular endosomal-like vesicles where it codistributes with integrin β1. Clustering of β1 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 β1 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.

Key words: Integrins, JAM, Leukocyte, Chemotaxis


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Related articles in JCS:

JAM-A – getting neutrophils unstuck

JCS 2009 122: 203. [Full Text]  





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