A β2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation.
β2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of β2-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the β2-integrin (TTT/AAA-β2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-β2-integrin KI dendritic cells, which leads to a failure of MRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of β2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of β2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function.
['Guenther|Carla|C|', 'Faisal|Imrul|I|', 'Uotila|Liisa M|LM|', 'Asens|Marc Llort|ML|', 'Harjunpää|Heidi|H|', 'Savinko|Terhi|T|', 'Öhman|Tiina|T|', 'Yao|Sean|S|', 'Moser|Markus|M|', 'Morris|Stephan W|SW|', 'Tojkander|Sari|S|', 'Fagerholm|Susanna Carola|SC|']
D000818:Animals D001696:Biomechanical Phenomena D018821:CD18 Antigens D002448:Cell Adhesion D002465:Cell Movement D002478:Cells, Cultured D003598:Cytoskeletal Proteins D003713:Dendritic Cells D020869:Gene Expression Profiling D063990:Gene Ontology D053263:Gene Regulatory Networks D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008822:Mice, Transgenic D026362:Serum Response Factor D015398:Signal Transduction D015534:Trans-Activators D020742:rhoA GTP-Binding Protein
MRTF-A SRF dendritic cells adhesion traction force LAD-III MKL-1