A β2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

Abstract

β2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of β 2 -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.

Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor

“…As transcription factors play critical roles in the regulation of gene expression, it is not surprising that alterations in the expression or activity of key transcription factors have been linked to the development of several cancers [ 40 ]. While it has long been known that signaling downstream of integrins can influence gene expression through the regulation of transcription [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ], roles for distinct integrins in the regulation of specific transcription factors remain underexplored.…”

Molecular Mechanisms of Leukocyte Migration and Its Potential Targeting—Lessons Learned From MKL1/SRF-Related Primary Immunodeficiency Diseases

“…MKL1 also regulated expression of genes involved in interferon signaling, such as STAT1 and several IFIT genes, but MKL1 deficiency also resulted in the upregulation of several genes ( 11 ). We have recently shown that in murine dendritic cells, MKL1 deletion did not only impact expression of cytoskeletal genes and genes of cytoskeletal regulators ( Fgr, Hck, Stmn1, Ckap2l, Anln, Tpm2, Tubb5 ), but also genes encoding for proteins involved in many other cellular pathways, such as lipid metabolism ( 12 ). Therefore, the effect of MKL1 on gene expression in immune cells appears to be cell type-specific.…”

“…The role of MKL1 in dendritic cell adhesion and migration has also been investigated. Interestingly, the MKL1/SRF pathway is downstream of beta2-integrins and beta2-integrin-mediated RhoA activation and F-actin polymerization in murine leukocytes ( 12 ). 3D migration of MKL1 knockout dendritic cells in response to CCL19 was normal, while (static) adhesion to integrin ligands was slightly reduced.…”

The Human Tissue-Engineered Cornea (hTEC): Recent Progress

“…The major signal transduction pathways activated by the integrins include the Janus kinase/signal transducers and activators of transcription (JAK/STAT) [ 331 ], mitogen-activated protein kinase (MAPK) [ 332 ], and phosphoinositide-3-kinases/protein kinase B (PI3K/AKT) pathways [ 333 , 334 ]. More recently, the β2 integrin subunit from the immune cells was also identified as an upstream regulator of the actin-regulated myocardin-related transcription factor A/serum response factor (MRTF-A/SRF) pathway in response to external cell stimuli that initiate F-actin polymerization downstream of RhoA activation [ 335 ]. However, in corneal wound healing, little is known about which pathway contributes the most to the healing process.…”