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

ID: 648320.0, MPI für molekulare Biomedizin / Yearbook 2013
Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury
Authors:Block, H.; Herter, J. M.; Rossaint, J.; Stadtmann, A.; Kliche, S.; Lowell, C. A.; Zarbock, A.
Date of Publication (YYYY-MM-DD):2012-02-13
Title of Journal:J Exp Med
Issue / Number:2
Start Page:407
End Page:421
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Neutrophils trigger inflammation-induced acute kidney injury (AKI), a frequent and potentially lethal occurrence in humans. Molecular mechanisms underlying neutrophil recruitment to sites of inflammation have proved elusive. In this study, we demonstrate that SLP-76 (SH2 domain-containing leukocyte phosphoprotein of 76 kD) and ADAP (adhesion and degranulation promoting adaptor protein) are involved in E-selectin-mediated integrin activation and slow leukocyte rolling, which promotes ischemia-reperfusion-induced AKI in mice. By using genetically engineered mice and transduced Slp76(-/-) primary leukocytes, we demonstrate that ADAP as well as two N-terminal-located tyrosines and the SH2 domain of SLP-76 are required for downstream signaling and slow leukocyte rolling. The Tec family kinase Bruton tyrosine kinase is downstream of SLP-76 and, together with ADAP, regulates PI3Kgamma (phosphoinositide 3-kinase-gamma)- and PLCgamma2 (phospholipase Cgamma2)-dependent pathways. Blocking both pathways completely abolishes integrin affinity and avidity regulation. Thus, SLP-76 and ADAP are involved in E-selectin-mediated integrin activation and neutrophil recruitment to inflamed kidneys, which may underlie the development of life-threatening ischemia-reperfusion-induced AKI in humans.
Free Keywords:Adaptor Proteins, Signal Transducing/genetics/immunology/*metabolism; Animals; Cell Line, Tumor; Class Ib Phosphatidylinositol 3-Kinase/metabolism; E-Selectin/metabolism; Genetic Vectors; Humans; Integrins/metabolism; Kidney/*blood supply/*immunology; Leukocyte Rolling/*immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neutrophils/*immunology; Peritonitis/chemically induced/immunology; Phospholipase C gamma/metabolism; Phosphoproteins/genetics/immunology/*metabolism; Protein-Tyrosine Kinases/metabolism; Reperfusion Injury/*immunology; Retroviridae; Thioglycolates/toxicity; Transduction, Genetic
External Publication Status:published
Document Type:Article
Communicated by:keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:%G eng
Identifiers:ISSN:1540-9538 (Electronic) 0022-1007 (Linking) %R 10.1... [ID No:1]
URL: [ID No:2]
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