title: CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules.
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.
authors: Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany. stefanie.kliche@med.ovgu.de
authors: Stefanie
authors: S
authors: Kliche
authors: Tim
authors: T
authors: Worbs
authors: Xiaoqian
authors: X
authors: Wang
authors: Janine
authors: J
authors: Degen
authors: Irene
authors: I
authors: Patzak
authors: Bernhard
authors: B
authors: Meineke
authors: Mauro
authors: M
authors: Togni
authors: Markus
authors: M
authors: Moser
authors: Annegret
authors: A
authors: Reinhold
authors: Friedemann
authors: F
authors: Kiefer
authors: Christian
authors: C
authors: Freund
authors: Reinhold
authors: R
authors: Förster
authors: Burkhart
authors: B
authors: Schraven
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism*; D000089804:Shelterin Complex; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016608:Talin / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000378:metabolism
chemical_list: C493340:APBB1IP protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C515370:CCR7 protein, human; C477322:FERMT3 protein, human; C491468:Fyb protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C454042:RASSF5 protein, human; D054400:Receptors, CCR7; C108336:SKAP1 protein, human; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; C518832:TLN1 protein, human; D016608:Talin; D034501:Telomere-Binding Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D020559:Monomeric GTP-Binding Proteins