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Vol. 16, Issue 12, 5793-5803, December 2005
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L/
2 Integrin, LFA-1, during Leukocyte Chemotaxis
* Unit of Leukocyte Biology, Vita-Salute San Raffaele University School of Medicine, DIBIT-Scientific Institute San Raffaele, 20132 Milan, Italy;
MicroSCoBiO Research Center and IFOM Center of Cell Oncology and Ultrastructure, Department of Experimental Medicine, University of Genova, 16132 Genoa, Italy; and
Raymond and Beverly Sackler Foundation Cardiovascular Laboratory, Sections of Cardiovascular Medicine and Immunobiology, Yale University School of Medicine, New Haven, CT 06536
Submitted May 10, 2005;
Revised September 20, 2005;
Accepted September 23, 2005
Monitoring Editor: Martin A. Schwartz
Cell migration entails the dynamic redistribution of adhesion receptors from the cell rear toward the cell front, where they form new protrusions and adhesions. This process may involve regulated endo-exocytosis of integrins. Here we show that in primary neutrophils unengaged 
L/
2 integrin (LFA-1) is internalized and rapidly recycled upon chemoattractant stimulation via a clathrin-independent, cholesterol-sensitive pathway involving dynamic partitioning into detergent-resistant membranes (DRM). Persistent DRM association is required for recycling of the internalized receptor because 1) >90% of endocytosed LFA-1 is associated with DRM, and a large fraction of the internalized receptor colocalizes intracellularly with markers of DRM and the recycling endocytic compartment; 2) a recycling-defective mutant (L/2Y735A) dissociates rapidly from DRM upon being endocytosed and is subsequently diverted into a late endosomal pathway; and 3) a dominant negative Rab11 mutant (Rab11S25N) induces intracellular accumulation of endocytosed L/2 and prevents its enrichment in chemoattractant-induced lamellipodia. Notably, chemokine-induced migration of neutrophils over immobilized ICAM-1 is abrogated by cholesterol-sequestering agents. We propose that DRM-associated endocytosis allows efficient retrieval of integrins, as they detach from their ligands, followed by polarized recycling to areas of the plasma membrane, such as lamellipodia, where they establish new adhesive interactions and promote outside-in signaling events.
Abbreviations used: cav-1, caveolin1; DRM, detergent-resistant membrane(s); fpR, N-formyl peptide receptor; GFP, green fluorescent protein; HAfpR-CHO, Chinese hamster ovary cells stably transfected with hemagglutinin-N-formyl peptide receptor; PMN, polymorphonuclear cell(s); TfR, transferrin receptor; WGA, wheat germ agglutinin.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
These authors contributed equally to this work.
Address correspondence to: Monica Fabbri (fabbri.monica{at}hsr.it).
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