Nucleocytoplasmic shuttling: a common theme in mechanotransduction

Abstract

Cells sense their mechanical and physical environment through diverse mechanisms, and these interactions specify a wide range of responses including growth, survival, migration and differentiation. Although much work has focused on dissecting the adhesive and structural components of the cell responsible for transducing external mechanical forces into biochemical signalling cascades, only recently have studies begun to examine how mechanical signals are transmitted to the nucleus and activate specific gene expression programmes. One necessary step in these processes is the transport of signalling molecules from the cytoplasm to the nucleus. The SRF (serum-response factor) and YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif) pathways are known mediators of this process in multiple cell types, including mesenchymal stem cells, keratinocytes, mammary epithelial cells and smooth muscle cells. In addition, recent evidence suggests a potential role for β-catenin and Smad signalling in mechanotransduction, but further mechanistic studies are needed to prove this hypothesis. As a model system, the epidermis of the skin is one tissue in which nucleocytoplasmic shuttling mediates cellular mechanosensing and is essential for tissue development, homoeostasis and repair. We propose that nuclear translocation is a common element of mechanotransduction conserved across multiple cell types and tissues.

Transcriptome of Cultured Lung Fibroblasts in Idiopathic Pulmonary Fibrosis: Meta-Analysis of Publically Available Microarray Datasets Reveals Repression of Inflammation and Immunity Pathways

“…Consistent for a role of CTGF in IPF, a recent open-label uncontrolled study suggested that a monoclonal antibody targeting CTGF, FG-3019, may be beneficial in a subset of IPF patients in terms of lung function decline and imaging-assessed fibrotic changes [23]. SRF is a transcription factor that is activated by the p38 MAP kinase pathway [24] and by increased extracellular matrix stiffness through mechanotransduction [25]. SRF is essential for collagen-1 expression by lung fibroblasts in vitro [26], while inhibition of the SRF pathway by the small molecule CCG-203971 attenuates lung fibrogenesis in the bleomycin-induced lung fibrosis model in mice [27].…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…To induce changes in the cell's gene expression program, signaling molecules regulated by external forces must be translocated from the cytoplasm into the nucleus and nucleocytoplasmic shuttling has been suggested as a common theme in mechanotransduction (Sharili and Connelly 2014). The SRF (serum-response factor) and YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif ) pathways are known mediators of this process in multiple cell types, including keratinocytes.…”

Dynamic transcription factor activity networks in response to independently altered mechanical and adhesive microenvironmental cues

“…A set of non-overlapping responses among the TFrs was also anticipated as RGD is thought to act exclusively through integrins 83 , yet mechanical signals can be relayed by multiple mechanisms, including G-protein coupled receptors, stretch-activated ion channels, actin-coupled TFs, and direct coupling to the nucleus 13, 17, 19, 31, 73 . Furthermore, integrins can coordinate with other receptors and/or signaling components to yield a sensitive and tailored response to the environmental factors, allowing differential responses to biochemical and biophysical features 84 .…”

“…For example, tumors are typically much stiffer than healthy tissue and this tissue rigidity may contribute to malignancy 13 . Many aspects of cellular differentiation and disease progression are mediated by interactions of extracellular matrix (ECM) with cytoskeleton-associated, cell membrane receptors that initiate complex cytosolic signaling cascades that lead to activated transcription factors (TFs) in the nucleus 3, 13, 17–19 . TFs are powerful regulators of cell phenotype, as evidenced by the development of methods to generate induced pluripotent stem cells by manipulating a few TFs 20 .…”