Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Initiation of fibronectin fibrillogenesis is an enzyme-dependent process

ABSTRACT: Fibronectin fibrillogenesis and mechanosensing both depend on integrin-mediated force transmission to the extracellular-matrix. However, force transmission is in itself dependent on fibrillogenesis, and fibronectin fibrils are found in soft embryos where high forces cannot be applied, suggesting that force cannot be the sole initiator of fibrillogenesis. Here we identify a novel nucleation step prior to force transmission, driven by fibronectin oxidation mediated by lysyl-oxidase enzyme family members. This oxidation induces fibronectin clustering that promotes early adhesion, alters cellular response to soft matrices, and enhances force transmission to the matrix. In contrast, absence of fibronectin oxidation abrogates fibrillogenesis, perturbs cell-matrix adhesion, and compromises mechanosensation. Moreover, fibronectin oxidation promotes cancer cells colony formation in soft agar as well as collective and single-cell migration. These results reveal a yet unidentified, force-independent enzyme-dependent mechanism that initiates fibronectin fibrillogenesis, establishing a critical step in cell adhesion and mechanosensing.

INSTRUMENT(S): Q Exactive HF, Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Haguy Wolfenson

LAB HEAD: Haguy Wolfenson

PROVIDER: PXD040505 | Pride | 2023-04-17

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Initiation of fibronectin fibrillogenesis is an enzyme-dependent process

Project description:Fibronectin fibrillogenesis and mechanosensing both depend on integrin-mediated force transmission to the extracellular-matrix. However, force transmission is in itself dependent on fibrillogenesis, and fibronectin fibrils are found in soft embryos where high forces cannot be applied, suggesting that force cannot be the sole initiator of fibrillogenesis. Here we identify a novel nucleation step prior to force transmission, driven by fibronectin oxidation mediated by lysyl-oxidase enzyme family members. This oxidation induces fibronectin clustering that promotes early adhesion, alters cellular response to soft matrices, and enhances force transmission to the matrix. In contrast, absence of fibronectin oxidation abrogates fibrillogenesis, perturbs cell-matrix adhesion, and compromises mechanosensation. Moreover, fibronectin oxidation promotes cancer cells colony formation in soft agar as well as collective and single-cell migration. These results reveal a yet unidentified, force-independent enzyme-dependent mechanism that initiates fibronectin fibrillogenesis, establishing a critical step in cell adhesion and mechanosensing.

2023-04-17 | PXD040900 | Pride

Sox2-dependent fibronectin fibrillogenesis controls directional collective migration of Schwann cells

Project description:The extracellular matrix is essential for tissue formation and regeneration through the control of cellular behavior. Deregulation of extracellular matrix components is associated to disease, including neurodegeneration. After peripheral nerve injury, Schwann cells guide regrowing axons to their targets. These glial cells migrate collectively and provide an extracellular environment to enable neural repair. How this occurs remains poorly understood. Here, we show that Sox2 controls fibronectin fibrillogenesis in Schwann cells to provide a highly oriented extracellular matrix, which supports their rapid collective migration with a continuous cellular flow. Sox2 directly activates fibronectin expression in Schwann cells, leading to an increase in fibrillogenesis and cellular huddling. Accordingly, loss of fibrillogenesis leads to glial disassembly and disorganized axon regrowth. In vivo, 7 days post nerve injury, we found that pro-regenerative Schwann cells co-express Sox2 and the EIIIA-containing fibronectin splicing isoform. This mechanism is conserved in mammals, including humans, but absent in zebrafish. Taken together, our results demonstrate that Sox2 directly controls fibrillogenesis and provide a novel mechanism for the modification of the environmental architecture by glial cells during neuronal repair.

2020-02-11 | GSE94590 | GEO

Rattus norvegicus

Project description:Sox2-dependent fibronectin fibrillogenesis controls directional collective migration of Schwann cells

| PRJNA371555 | ENA

Tensin3 interaction with talin drives formation of fibronectin-associated fibrillar adhesions

Project description:The formation of healthy tissue involves continuous remodelling of the extracellular matrix (ECM). Whilst it is known that this requires integrin-associated cell-ECM adhesion sites (CMAs) and actomyosin-mediated forces, the underlying mechanisms remain unclear. Here we examine how tensin3 contributes to formation of fibrillar adhesions (FBs) and fibronectin fibrillogenesis. Using BioID mass spectrometry and a mitochondrial targeting assay, we establish that tensin3 associates with the mechanosensors talin and vinculin. We show that the talin R11 rod domain binds directly to a helical motif within the central intrinsically disordered region (IDR) of tensin3, whilst vinculin binds indirectly to tensin3 via talin. Using CRISPR knock-out cells in combination with defined tensin3 mutations, we show (i) that tensin3 is critical for formation of alpha5 beta1-integrin FBs and for fibronectin fibrillogenesis, and (ii) the talin/tensin3 interaction drives this process, with vinculin acting to potentiate it.

2022-09-09 | PXD026343 | Pride

YAP regulates cell mechanics by controlling focal adhesion assembly

Project description:Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described so far through a hierarchical model in which elements of Hippo pathway are under the control of Focal Adhesions (FAs). Here we unveiled the molecular mechanism by which cell spreading and RhoA GTPase control FA formation through YAP to stabilize the anchorage of actin cytoskeleton to cell membrane. This mechanism required YAP co-transcriptional function and involved the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity led to the modification of cell mechanics, force development, adhesion strength, determined cell shaping, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify Hippo effector as the key determinant of cell mechanics in response to ECM cues.

2017-05-17 | E-MTAB-5217 | biostudies-arrayexpress

Cancer-associated fibroblasts actively compress cancer cells and modulate mechanotransduction

Project description:During tumor progression, cancer-associated fibroblasts (CAFs) accumulate in tumors and produce an excessive extracellular matrix (ECM), forming a capsule that enwraps cancer cells. This capsule acts as a barrier that restricts tumor growth leading to the buildup of intratumoral pressure. Combining genetic and physical manipulations in vivo with microfabrication and force measurements in vitro, we found that the CAFs capsule is not a passive barrier but instead actively compresses cancer cells using actomyosin contractility. Abrogation of CAFs contractility in vivo leads to the dissipation of compressive forces and impairment of capsule formation. By mapping CAF force patterns in 3D, we show that compression is a CAF-intrinsic property independent of cancer cell growth. Supracellular coordination of CAFs is achieved through fibronectin cables that serve as scaffolds allowing force transmission. Cancer cells mechanosense CAF compression, resulting in an altered localization of the transcriptional regulator YAP and a decrease in proliferation. Our study unveils that the contractile capsule actively compresses cancer cells, modulates their mechanical signaling, and reorganizes tumor morphology.

2023-09-11 | GSE242846 | GEO

Molecular design of the γδ T cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing

Project description:High acuity αβT cell receptor (TCR) recognition of peptides bound to MHC molecules (pMHC) requires mechanosensing, a process whereby piconewton (pN) bioforces exert physical load on αβTCR-pMHC bonds to dynamically alter their lifetimes and foster digital sensitivity cellular signaling. While mechanotransduction is operative for both αβTCRs and preTCRs within the αβT-lineage, its role in γδT cells is unknown. Here we show that the human DP10.7 γδTCR specific for the sulfoglycolipid sulfatide bound to CD1d only sustains significant load and undergoes force-induced structural transitions when the binding interface-distal γδ constant domain (C) module is replaced with that of αβ. The chimeric γδ-αβTCR also signals more robustly than the wild-type γδTCR as revealed by RNA-seq analysis of TCR-transduced Rag2-/- thymocytes, consistent with structural, single molecule and molecular dynamics studies reflective of γδTCRs as mediating recognition via a more canonical immunoglobulin-like receptor interaction. Absence of robust, force-related catch bonds as well as γδTCR structural transitions implies that γδT cells do not use mechanosensing for ligand recognition. This distinction is consonant with the fact that their innate-type ligands, including markers of cellular stress, are expressed at high copy number relative to sparse pMHC ligands of αβT cells arrayed on activating target cells. We posit that mechanosensing emerged over ~200 million years of vertebrate evolution to fulfill indispensable adaptive immune recognition requirements for pMHC in the αβT cell lineage that are unnecessary for the γδ T cell lineage mechanism of non-pMHC ligand detection.

2021-06-22 | GSE165297 | GEO

Potential interactors of alpha-tubulin acetyltransferase 1 (αTAT1/MEC17)

Project description:Cell adhesion to the extracellular matrix occurs through integrin-mediated focal adhesions, which sense the mechanical properties of the substrate and impact cellular functions such as cell migration. Mechanotransduction at focal adhesions affects the actomyosin network and contributes to cell migration. Despite being key players in cell adhesion and migration, the role of microtubules in mechanotransduction has been overlooked. Here, we show that substrate rigidity increases microtubule acetylation through β1 integrin signalling in primary rat astrocytes. Moreover, αTAT1, the enzyme responsible for microtubule acetylation, interacts with a major mechanosensing focal adhesion protein, Talin, and is able to tune the distribution of focal adhesions depending on the matrix rigidity. αTAT1 also reorganises the actomyosin network, increases traction force generation and cell migration speed on stiff substrates. Mechanistically, acetylation of microtubules promotes the release of microtubule-associated RhoGEF, GEF-H1 into the cytoplasm, which then leads to RhoA activation and high actomyosin contractility. Thus, we propose a novel feedback loop involving a crosstalk between microtubules and actin in mechanotransduction at focal adhesions whereby, cells sense the rigidity of the substrate through integrin-mediated adhesions, modulate their levels of microtubule acetylation, which then controls the actomyosin cytoskeleton and force transmission on the substrate to promote mechanosensitive cell migration.

2021-11-02 | PXD015871 | Pride

Mesenchymal stem cell integrin-associated complexes

Project description:The composition and stiffness of the extracellular matrix (ECM) environment that surrounds Multipotent mesenchymal stem cells (MSCs) stem cells dictates transcriptional programming, thereby affecting stem cell lineage decision-making. Cells sense force between themselves and their microenvironment controlling the capability of MSCs to differentiate into adipocytes, osteocytes and chondrocytes. Force sensing is transmitted by integrin receptors and their associated adhesion signalling complexes. To identify regulators of MSC force sensing we sought to catalogue MSC adhesion complex composition. Therefore we isolated integrin-associated adhesion complexes formed in MSCs plated on the ECM ligand fibronectin. We identifed proteins using mass spectrometry that define a MSC specific subset of adhesion complex proteins consisting of key linkages to the actin cytoskeleton together with integrin signalling and force sensing components.

2016-07-20 | MSV000079956 | MassIVE

Mesenchymal stem cell integrin-associated complexes

2015-07-20 | PXD001809 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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