Abstract
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55 module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T-cell motility in vivo. This is probably because of a defect in CCR7-mediated adhesion that affects both affinity and avidity regulation of LFA-1. Further analysis of how the ADAP/SKAP55 module regulates CCR7-induced integrin activation revealed that 2 independent pools of the module are expressed in T cells. One pool interacts with a RAPL/Mst1 complex, whereas the other pool is linked to a RIAM/Mst1/Kindlin-3 complex. Importantly, both the RAPL/Mst1 and the RIAM/Mst1/Kindlin-3 complexes require ADAP/SKAP55 for binding to LFA-1 upon CCR7 stimulation. Hence, 2 independent ADAP/SKAP55 modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Apoptosis
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Apoptosis Regulatory Proteins
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Blotting, Western
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Cell Adhesion
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Cell Movement
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Cell Proliferation
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Flow Cytometry
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Gene Expression Regulation*
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Hepatocyte Growth Factor / metabolism
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Humans
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Immunoprecipitation
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Lymphocyte Function-Associated Antigen-1 / metabolism*
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Monomeric GTP-Binding Proteins / metabolism
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Neoplasm Proteins / metabolism
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Phosphoproteins / metabolism*
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Proto-Oncogene Proteins / metabolism
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Receptors, CCR7 / metabolism*
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Shelterin Complex
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Signal Transduction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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Talin / metabolism
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Telomere-Binding Proteins / metabolism
Substances
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APBB1IP protein, human
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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CCR7 protein, human
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FERMT3 protein, human
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Fyb protein, mouse
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Lymphocyte Function-Associated Antigen-1
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Membrane Proteins
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Neoplasm Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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RASSF5 protein, human
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Receptors, CCR7
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SKAP1 protein, human
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Shelterin Complex
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TERF2IP protein, human
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TLN1 protein, human
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Talin
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Telomere-Binding Proteins
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macrophage stimulating protein
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Hepatocyte Growth Factor
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Monomeric GTP-Binding Proteins