An official website of the United States government
In epithelia, breakdown of tensional homeostasis is closely associated with E-cadherin dysfunction and disruption of tissue function and integrity. In this study, we investigated the effect of E-cadherin mutations affecting distinct protein domains on tensional homeostasis of gastric cancer cells. We used micropattern traction microscopy to measure temporal fluctuations of cellular traction forces in AGS cells transfected with the wild-type E-cadherin or with variants affecting the extracellular, the juxtamembrane, and the intracellular domains of the protein. We focused on the dynamic aspect of tensional homeostasis, namely the ability of cells to maintain a consistent level of tension, with low temporal variability around a set point. Cells were cultured on hydrogels micropatterned with different extracellular matrix (ECM) proteins to test whether the ECM adhesion impacts cell behavior. A combination of Fibronectin and Vitronectin was used as a substrate that promotes the adhesive ability of E-cadherin dysfunctional cells, whereas Collagen VI was used to test an unfavorable ECM condition. Our results showed that mutations affecting distinct E-cadherin domains influenced differently cell tensional homeostasis, and pinpointed the juxtamembrane and intracellular regions of E-cadherin as the key players in this process. Furthermore, Fibronectin and Vitronectin might modulate cancer cell behavior towards tensional homeostasis.
more »
« less
How Do Cells Adapt? Stories Told in Landscapes
Cells adapt to changing environments. Perturb a cell and it returns to a point of homeostasis. Perturb a population and it evolves toward a fitness peak. We review quantitative models of the forces of adaptation and their visualizations on landscapes. While some adaptations result from single mutations or few-gene effects, others are more cooperative, more delocalized in the genome, and more universal and physical. For example, homeostasis and evolution depend on protein folding and aggregation, energy and protein production, protein diffusion, molecular motor speeds and efficiencies, and protein expression levels. Models provide a way to learn about the fitness of cells and cell populations by making and testing hypotheses.
more »
« less
- PAR ID:
- 10234028
- Date Published:
- Journal Name:
- Annual Review of Chemical and Biomolecular Engineering
- Volume:
- 11
- Issue:
- 1
- ISSN:
- 1947-5438
- Page Range / eLocation ID:
- 155 to 182
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Tensional homeostasis is a phenomenon of fundamental importance in mechanobiology. It refers to the ability of organs, tissues, and cells to respond to external disturbances by maintaining a homeostatic (set point) level of mechanical stress (tension). It is well documented that breakdown in tensional homeostasis is the hallmark of progression of diseases, including cancer and atherosclerosis. In this review, we surveyed quantitative studies of tensional homeostasis with the goal of providing characterization of this phenomenon across a broad range of length scales, from the organ level to the subcellular level. We considered both static and dynamics approaches that have been used in studies of this phenomenon. Results that we found in the literature and that we obtained from our own investigations suggest that tensional homeostasis is an emergent phenomenon driven by collective rheostatic mechanisms associated with focal adhesions, and by a collective action of cells in multicellular forms, whose impact on tensional homeostasis is cell type-dependent and cell microenvironment-dependent. Additionally, the finding that cadherins, adhesion molecules that are important for formation of cell–cell junctions, promote tensional homeostasis even in single cells, demonstrates their relevance as a signaling moiety.more » « less
-
The ability of cells to maintain a constant level of cytoskeletal tension in response to external and internal disturbances is referred to as tensional homeostasis. It is essential for the normal physiological function of cells and tissues, and for protection against disease progression, including atherosclerosis and cancer. In previous studies, we defined tensional homeostasis as the ability of cells to maintain a consistent level of cytoskeletal tension with low temporal fluctuations. In those studies, we measured temporal fluctuations of cell-substrate traction forces in clusters of endothelial cells and of fibroblasts. We observed those temporal fluctuations to decrease with increasing cluster size in endothelial cells, but not in fibroblasts. We quantified temporal fluctuation, and thus homeostasis, through the coefficient of variation (CV) of the traction field; the lower the value of CV, the closer the cell is to the state of tensional homeostasis. This metric depends on correlation between individual traction forces. In this study, we analyzed the contribution of correlation between traction forces on traction field CV in clusters of endothelial cells and fibroblasts using experimental data that we had obtained previously. Results of our analysis showed that positive correlation between traction forces was detrimental to homeostasis, and that it was cell type-dependent.more » « less
-
Protein stability is subject to environmental perturbations such as pressure and crowding, as well as sticking to other macromolecules and quinary structure. Thus, the environment inside and outside the cell plays a key role in how proteins fold, interact, and function on the scale from a few molecules to macroscopic ensembles. This review discusses three aspects of protein phase diagrams: first, the relevance of phase diagrams to protein folding and functionin vitroand in cells; next, how the evolution of protein surfaces impacts on interaction phase diagrams; and finally, how phase separation plays a role on much larger length‐scales than individual proteins or oligomers, when liquid phase‐separated regions form to assist protein function and cell homeostasis.more » « less
-
Abstract Possessing only essential genes, a minimal cell can reveal mechanisms and processes that are critical for the persistence and stability of life1,2. Here we report on how an engineered minimal cell3,4contends with the forces of evolution compared with theMycoplasma mycoidesnon-minimal cell from which it was synthetically derived. Mutation rates were the highest among all reported bacteria, but were not affected by genome minimization. Genome streamlining was costly, leading to a decrease in fitness of greater than 50%, but this deficit was regained during 2,000 generations of evolution. Despite selection acting on distinct genetic targets, increases in the maximum growth rate of the synthetic cells were comparable. Moreover, when performance was assessed by relative fitness, the minimal cell evolved 39% faster than the non-minimal cell. The only apparent constraint involved the evolution of cell size. The size of the non-minimal cell increased by 80%, whereas the minimal cell remained the same. This pattern reflected epistatic effects of mutations inftsZ, which encodes a tubulin-homologue protein that regulates cell division and morphology5,6. Our findings demonstrate that natural selection can rapidly increase the fitness of one of the simplest autonomously growing organisms. Understanding how species with small genomes overcome evolutionary challenges provides critical insights into the persistence of host-associated endosymbionts, the stability of streamlined chassis for biotechnology and the targeted refinement of synthetically engineered cells2,7–9.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1146/annurev-chembioeng-011720-103410
