Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

An optogenetic model reveals cell shape regulation through FAK and fascin.

ABSTRACT: Cell shape regulation is important, but the mechanisms that govern shape are not fully understood, in part due to limited experimental models in which cell shape changes and underlying molecular processes can be rapidly and non-invasively monitored in real time. Here, we used an optogenetic tool to activate RhoA in the middle of mononucleated macrophages to induce contraction, resulting in a side with the nucleus that retained its shape and a non-nucleated side that was unable to maintain its shape and collapsed. In cells overexpressing focal adhesion kinase (FAK; also known as PTK2), the non-nucleated side exhibited a wide flat morphology and was similar in adhesion area to the nucleated side. In cells overexpressing fascin, an actin-bundling protein, the non-nucleated side assumed a spherical shape and was similar in height to the nucleated side. This effect of fascin was also observed in fibroblasts even without inducing furrow formation. Based on these results, we conclude that FAK and fascin work together to maintain cell shape by regulating adhesion area and height, respectively, in different cell types. This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Castillo-Badillo JA

PROVIDER: S-EPMC8277139 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Cell shape regulation through mechanosensory feedback control.

Project description:Cells undergo controlled changes in morphology in response to intracellular and extracellular signals. These changes require a means for sensing and interpreting the signalling cues, for generating the forces that act on the cell's physical material, and a control system to regulate this process. Experiments on Dictyostelium amoebae have shown that force-generating proteins can localize in response to external mechanical perturbations. This mechanosensing, and the ensuing mechanical feedback, plays an important role in minimizing the effect of mechanical disturbances in the course of changes in cell shape, especially during cell division, and likely in other contexts, such as during three-dimensional migration. Owing to the complexity of the feedback system, which couples mechanical and biochemical signals involved in shape regulation, theoretical approaches can guide further investigation by providing insights that are difficult to decipher experimentally. Here, we present a computational model that explains the different mechanosensory and mechanoresponsive behaviours observed in Dictyostelium cells. The model features a multiscale description of myosin II bipolar thick filament assembly that includes cooperative and force-dependent myosin-actin binding, and identifies the feedback mechanisms hidden in the observed mechanoresponsive behaviours of Dictyostelium cells during micropipette aspiration experiments. These feedbacks provide a mechanistic explanation of cellular retraction and hence cell shape regulation.

| S-EPMC4535415 | biostudies-literature

Fascin Activates ?-Catenin Signaling and Promotes Breast Cancer Stem Cell Function Mainly Through Focal Adhesion Kinase (FAK): Relation With Disease Progression.

Project description:Cancer stem cells (CSCs), a rare population of tumor cells with high self-renewability potential, have gained increasing attention due to their contribution to chemoresistance and metastasis. We have previously demonstrated a critical role for the actin-bundling protein (fascin) in mediating breast cancer chemoresistance through activation of focal adhesion kinase (FAK). The latter is known to trigger the ?-catenin signaling pathway. Whether fascin activation of FAK would ultimately trigger ?-catenin signaling pathway has not been elucidated. Here, we assessed the effect of fascin manipulation in breast cancer cells on triggering ?-catenin downstream targets and its dependence on FAK. Gain and loss of fascin expression showed its direct effect on the constitutive expression of ?-catenin downstream targets and enhancement of self-renewability. In addition, fascin was essential for glycogen synthase kinase 3? inhibitor-mediated inducible expression and function of the ?-catenin downstream targets. Importantly, fascin-mediated constitutive and inducible expression of ?-catenin downstream targets, as well as its subsequent effect on CSC function, was at least partially FAK dependent. To assess the clinical relevance of the in vitro findings, we evaluated the consequence of fascin, FAK, and ?-catenin downstream target coexpression on the outcome of breast cancer patient survival. Patients with coexpression of fascinhigh and FAKhigh or high ?-catenin downstream targets showed the worst survival outcome, whereas in fascinlow, patient coexpression of FAKhigh or high ?-catenin targets had less significant effect on the survival. Altogether, our data demonstrated the critical role of fascin-mediated ?-catenin activation and its dependence on intact FAK signaling to promote breast CSC function. These findings suggest that targeting of fascin-FAK-?-catenin axis may provide a novel therapeutic approach for eradication of breast cancer from the root.

| S-EPMC7186340 | biostudies-literature

Sulfiredoxin promotes cancer cell invasion through regulation of the miR143-Fascin axis

Project description:including datasets of DNA microarrays and miRNA arrays from HCT116 control and HCT-ShSrx cells

2022-04-03 | GSE196668 | GEO

FXR promotes endothelial cell motility through coordinated regulation of FAK and MMP-9.

Project description:Farnesoid X Receptor (FXR) mediates important signaling functions of bile acids in diverse cell types including those residing in the vascular wall. Indeed, recent work has identified FXR as a potential regulator of vascular structure and function in part through transcriptional activation of MMP-9. However, the signal transduction pathways linking bile acids to changes in actin cytoskeleton that are responsible for bile acid-induced vascular cell migration remain unexplored.The FXR agonist and prototypical bile acid, chenodeoxycholic acid (CDCA), significantly increased endothelial cell (EC) motility, as analyzed by time lapse video microscopy, and tube formation, an in vitro correlate for angiogenesis. Increased cell motility was associated with prominent increases in focal adhesion (FA) plaques and was inhibited by FXR or MMP-9 siRNA, indicating a FXR-MMP-9-dependency of this signaling pathway. Mechanistically, incubation of cells with CDCA was associated with phosphorylation of a key FA protein, Focal Adhesion Kinase (FAK) at Y397 but not at Y576/577, or Y925. Studies using a site-specific phosphorylation mutant (phosphodeficient) of FAK revealed that FAK phosphorylation at tyrosine residue -397 was required for CDCA induced activation of the downstream FA assembly protein, paxillin. Lastly, siRNA-based silencing of FAK as well as phosphodeficient FAK mutant inhibited CDCA induced upregulation of MMP-9, cell motility, and vascular tube formation.Thus, this study demonstrates a pivotal role for FAK in the process of FXR-induced and MMP-9-dependent EC motility and vascular tube formation.

| S-EPMC2697392 | biostudies-other

Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness.

Project description:Breast tumor progression is accompanied by changes in the surrounding extracellular matrix (ECM) that increase stiffness of the microenvironment. Mammary epithelial cells engage regulatory pathways that permit dynamic responses to mechanical cues from the ECM. Here, we identify a SLIT2/ROBO1 signaling circuit as a key regulatory mechanism by which cells sense and respond to ECM stiffness to preserve tensional homeostasis. We observed that Robo1 ablation in the developing mammary gland compromised actin stress fiber assembly and inhibited cell contractility to perturb tissue morphogenesis, whereas SLIT2 treatment stimulated Rac and increased focal adhesion kinase activity to enhance cell tension by maintaining cell shape and matrix adhesion. Further investigation revealed that a stiff ECM increased Robo1 levels by down-regulating miR-203. Consistently, patients whose tumor expressed a low miR-203/high Robo1 expression pattern exhibited a better overall survival prognosis. These studies show that cells subjected to stiffened environments up-regulate Robo1 as a protective mechanism that maintains cell shape and facilitates ECM adherence.

| S-EPMC4792073 | biostudies-literature

Regulation of endogenous transmembrane receptors through optogenetic Cry2 clustering.

Project description:Transmembrane receptors are the predominant conduit through which cells sense and transduce extracellular information into intracellular biochemical signals. Current methods to control and study receptor function, however, suffer from poor resolution in space and time and often employ receptor overexpression, which can introduce experimental artefacts. We report a genetically encoded approach, termed Clustering Indirectly using Cryptochrome 2 (CLICR), for spatiotemporal control over endogenous transmembrane receptor activation, enabled through the optical regulation of target receptor clustering and downstream signalling using noncovalent interactions with engineered Arabidopsis Cryptochrome 2 (Cry2). CLICR offers a modular platform to enable photocontrol of the clustering of diverse transmembrane receptors including fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and integrins in multiple cell types including neural stem cells. Furthermore, light-inducible manipulation of endogenous receptor tyrosine kinase (RTK) activity can modulate cell polarity and establish phototaxis in fibroblasts. The resulting spatiotemporal control over cellular signalling represents a powerful new optogenetic framework for investigating and controlling cell function and fate.

| S-EPMC4408875 | biostudies-literature

SEPT9_i1 regulates human breast cancer cell motility through cytoskeletal and RhoA/FAK signaling pathway regulation.

Project description:Increasing cell mobility is the basis of tumor invasion and metastasis, and is therefore a therapeutic target for preventing the spread of many types of cancer. Septins are a family of cytoskeletal proteins with GTPase activity, and play a role in many important cellular functions, including cell migration. SEPT9 isoform 1 protein (SEPT9_i1) has been associated with breast tumor development and the enhancement of cell migration; however, the exact mechanism of how SEPT9_i1 might affect breast cancer progression remains to be elucidated. Here, we report that the expression of SEPT9_i1 positively correlated with paxillin, and both were significantly upregulated in invasive breast cancer tissues of patients with lymph node metastases. Lentivirus-mediated shRNA knockdown of SEPT9 in MCF-7 cells diminished tumor cell migration, focal adhesion (FA) maturation and the expression of β-actin, β-tubulin, Cdc42, RhoA, and Rac, whereas overexpression of SEPT9_i1 in SEPT9-knockdown MCF-7 cells promoted cell migration, FA maturation and relevant protein expression. Furthermore, overexpression of SEPT9_i1 in MCF-7 cells markedly increased FAK/Src/paxillin signaling, at least in part through RhoA/ROCK1 upstream activation. Transcriptome profiling suggested that SEPT9_i1 may directly affect "Focal adhesion" and "Regulation of actin cytoskeleton" signaling mechanisms. Finally, overexpression of SEPT9_i1 markedly enhanced lung metastases in vivo 6 weeks after tumor inoculation. These findings suggest that a mechanism of Septin-9-induced aberrant cancer cell migration is through cytoskeletal regulation and FA modulation, and encourages the use of SEPT9 as novel therapeutic target in the prevention of tumor metastasis.

| S-EPMC6763430 | biostudies-literature

FAK signalling controls insulin sensitivity through regulation of adipocyte survival.

Project description:Focal adhesion kinase (FAK) plays a central role in integrin signalling, which regulates growth and survival of tumours. Here we show that FAK protein levels are increased in adipose tissue of insulin-resistant obese mice and humans. Disruption of adipocyte FAK in mice or in 3T3 L1 cells decreases adipocyte survival. Adipocyte-specific FAK knockout mice display impaired adipose tissue expansion and insulin resistance on prolonged metabolic stress from a high-fat diet or when crossed on an obese db/db or ob/ob genetic background. Treatment of these mice with a PPAR? agonist does not restore adiposity or improve insulin sensitivity. In contrast, inhibition of apoptosis, either genetically or pharmacologically, attenuates adipocyte death, restores normal adiposity and improves insulin sensitivity. Together, these results demonstrate that FAK is required for adipocyte survival and maintenance of insulin sensitivity, particularly in the context of adipose tissue expansion as a result of caloric excess.

| S-EPMC5303880 | biostudies-other

Differential regulation of cell motility and invasion by FAK.

Project description:Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK-/- fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK-/- cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK-/- v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK-Src-p130Cas-Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways.

| S-EPMC2173366 | biostudies-other

Optogenetic regulation of transcription.

Project description:Optogenetics has become widely recognized for its success in real-time control of brain neurons by utilizing non-mammalian photosensitive proteins to open or close membrane channels. Here we review a less well known type of optogenetic constructs that employs photosensitive proteins to transduce the signal to regulate gene transcription, and its possible use in medicine. One of the problems with existing gene therapies is that they could remain active indefinitely while not allowing regulated transgene production on demand. Optogenetic regulation of transcription (ORT) could potentially be used to regulate the production of a biological drug in situ, by repeatedly applying light to the tissue, and inducing expression of therapeutic transgenes when needed. Red and near infrared wavelengths, which are capable of penetration into tissues, have potential for therapeutic applications. Existing ORT systems are reviewed herein with these considerations in mind.

| S-EPMC5998900 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data