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          Institute: MPI für molekulare Biomedizin     Collection: Yearbook 2013     Display Documents



  history
ID: 648350.0, MPI für molekulare Biomedizin / Yearbook 2013
Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation
Authors:Lefort, C. T.; Rossaint, J.; Moser, M.; Petrich, B. G.; Zarbock, A.; Monkley, S. J.; Critchley, D. R.; Ginsberg, M. H.; Fassler, R.; Ley, K.
Date of Publication (YYYY-MM-DD):2012-05-03
Title of Journal:Blood
Volume:119
Issue / Number:18
Start Page:4275
End Page:4282
Review Status:Internal review
Audience:Not Specified
Abstract / Description:In inflammation, neutrophils and other leukocytes roll along the microvascular endothelium before arresting and transmigrating into inflamed tissues. Arrest requires conformational activation of the integrin lymphocyte function-associated antigen-1 (LFA-1). Mutations of the FERMT3 gene encoding kindlin-3 underlie the human immune deficiency known as leukocyte adhesion deficiency-III. Both kindlin-3 and talin-1, another FERM domain-containing cytoskeletal protein, are required for integrin activation, but their individual roles in the induction of specific integrin conformers are unclear. Here, we induce differential LFA-1 activation in neutrophils through engagement of the selectin ligand P-selectin glycoprotein ligand-1 or the chemokine receptor CXCR2. We find that talin-1 is required for inducing LFA-1 extension, which corresponds to intermediate affinity and induces neutrophil slow rolling, whereas both talin-1 and kindlin-3 are required for induction of the high-affinity conformation of LFA-1 with an open headpiece, which results in neutrophil arrest. In vivo, both slow rolling and arrest are defective in talin-1-deficient neutrophils, whereas only arrest is defective in kindlin-3-deficient neutrophils. We conclude that talin-1 and kindlin-3 serve distinct functions in LFA-1 activation.
Free Keywords:Animals; Bone Marrow Transplantation; Cell Adhesion; Chemotaxis, Leukocyte/*physiology; Cytoskeletal Proteins/antagonists & inhibitors/genetics/*physiology; Green Fluorescent Proteins/analysis; HL-60 Cells; Humans; Intercellular Adhesion Molecule-1/metabolism; K562 Cells; Lymphocyte Function-Associated Antigen-1/chemistry/*metabolism; Membrane Proteins/antagonists & inhibitors/genetics/physiology; Mice; Mice, Inbred C57BL; Neoplasm Proteins/antagonists & inhibitors/genetics/physiology; Neutrophils/*metabolism; Peritonitis/chemically induced/immunology/metabolism; Protein Binding; Protein Conformation; RNA Interference; RNA, Small Interfering/pharmacology; Radiation Chimera; Specific Pathogen-Free Organisms; Talin/antagonists & inhibitors/genetics/*physiology
External Publication Status:published
Document Type:Article
Communicated by:keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:%G eng
Identifiers:ISSN:1528-0020 (Electronic) 0006-4971 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/22431571 [ID No:2]
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