Coregulation of Fibronectin Signaling and Matrix Contraction by Tenascin-C and Syndecan-4

Syndecan-4 is a ubiquitously expressed heparan sulfate proteoglycan that modulates cell interactions with the extracellular matrix. It is transiently up-regulated during tissue repair by cells that mediate wound healing. Here, we report that syndecan-4 is essential for optimal fibroblast response to the three-dimensional fibrin-fibronectin provisional matrix that is deposited upon tissue injury. Interference with syndecan-4 function inhibits matrix contraction by preventing cell spreading, actin stress fiber formation, and activation of focal adhesion kinase and RhoA mediated-intracellular signaling pathways. Tenascin-C is an extracellular matrix protein that regulates cell response to fibronectin within the provisional matrix. Syndecan-4 is also required for tenascin-C action. Inhibition of syndecan-4 function suppresses tenascin-C activity and overexpression of syndecan-4 circumvents the effects of tenascin-C. In this way, tenascin-C and syndecan-4 work together to control fibroblast morphology and signaling and regulate events such as matrix contraction that are essential for efficient tissue repair.

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Immunomodulatory role of the extracellular matrix protein tenascin-C in neuroinflammation

Biochemical Society Transactions ◽

10.1042/bst20190081 ◽

2019 ◽

Vol 47 (6) ◽

pp. 1651-1660 ◽

Cited By ~ 5

Author(s):

Susanne Wiemann ◽

Jacqueline Reinhard ◽

Andreas Faissner

Keyword(s):

Extracellular Matrix ◽

Intracellular Signaling ◽

Matrix Protein ◽

Dynamic Network ◽

Adaptor Proteins ◽

Extracellular Matrix Protein ◽

Tenascin C ◽

Pathological Conditions ◽

Main Components

The extracellular matrix (ECM) consists of a dynamic network of various macromolecules that are synthesized and released by surrounding cells into the intercellular space. Glycoproteins, proteoglycans and fibrillar proteins are main components of the ECM. In addition to general functions such as structure and stability, the ECM controls several cellular signaling pathways. In this context, ECM molecules have a profound influence on intracellular signaling as receptor-, adhesion- and adaptor-proteins. Due to its various functions, the ECM is essential in the healthy organism, but also under pathological conditions. ECM constituents are part of the glial scar, which is formed in several neurodegenerative diseases that are accompanied by the activation and infiltration of glia as well as immune cells. Remodeling of the ECM modulates the release of pro- and anti-inflammatory cytokines affecting the fate of immune, glial and neuronal cells. Tenascin-C is an ECM glycoprotein that is expressed during embryonic central nervous system (CNS) development. In adults it is present at lower levels but reappears under pathological conditions such as in brain tumors, following injury and in neurodegenerative disorders and is highly associated with glial reactivity as well as scar formation. As a key modulator of the immune response during neurodegeneration in the CNS, tenascin-C is highlighted in this mini-review.

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Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma

Cancer Research ◽

10.1158/0008-5472.can-18-3125 ◽

2019 ◽

Vol 79 (10) ◽

pp. 2697-2708 ◽

Cited By ~ 5

Author(s):

Ding Ma ◽

Senquan Liu ◽

Bachchu Lal ◽

Shuang Wei ◽

Shuyan Wang ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Loss Of Function ◽

Tenascin C

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Faculty Opinions recommendation of Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717952874.793458358 ◽

2012 ◽

Author(s):

Suneel Apte

Keyword(s):

Bone Marrow ◽

Extracellular Matrix ◽

Matrix Protein ◽

Bone Marrow Microenvironment ◽

Extracellular Matrix Protein ◽

Tenascin C

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The c-Jun-induced transformation process involves complex regulation of tenascin-C expression.

Molecular and Cellular Biology ◽

10.1128/mcb.17.6.3202 ◽

1997 ◽

Vol 17 (6) ◽

pp. 3202-3209 ◽

Cited By ~ 43

Author(s):

A Mettouchi ◽

F Cabon ◽

N Montreau ◽

V Dejong ◽

P Vernier ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Cell Attachment ◽

Matrix Composition ◽

Expression Vectors ◽

Extracellular Matrix Protein ◽

Cdna Clones ◽

Tenascin C ◽

Nf Kappab ◽

Factor C

In cooperation with an activated ras oncogene, the site-dependent AP-1 transcription factor c-Jun transforms primary rat embryo fibroblasts (REF). Although signal transduction pathways leading to activation of c-Jun proteins have been extensively studied, little is known about c-Jun cellular targets. We identified c-Jun-upregulated cDNA clones homologous to the tenascin-C gene by differential screening of a cDNA library from REF. This tightly regulated gene encodes a rare extracellular matrix protein involved in cell attachment and migration and in the control of cell growth. Transient overexpression of c-Jun induced tenascin-C expression in primary REF and in FR3T3, an established fibroblast cell line. Surprisingly, tenascin-C synthesis was repressed after stable transformation by c-Jun compared to that in the nontransformed parental cells. As assessed by using the tenascin-C (-220 to +79) promoter fragment cloned in a reporter construct, the c-Jun-induced transient activation is mediated by two binding sites: one GCN4/AP-1-like site, at position -146, and one NF-kappaB site, at position -210. Furthermore, as demonstrated by gel shift experiments and cotransfections of the reporter plasmid and expression vectors encoding the p65 subunit of NF-kappaB and c-Jun, the two transcription factors bind and synergistically transactivate the tenascin-C promoter. We previously described two other extracellular matrix proteins, SPARC and thrombospondin-1, as c-Jun targets. Thus, our results strongly suggest that the regulation of the extracellular matrix composition plays a central role in c-Jun-induced transformation.

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Efemp1 modulates elastic fiber formation and mechanics of the extrahepatic bile duct

10.1101/2021.12.05.471313 ◽

2021 ◽

Author(s):

Jessica Llewellyn ◽

Emilia Roberts ◽

Chengyang Liu ◽

Ali Naji ◽

Richard K. Assoian ◽

...

Keyword(s):

Extracellular Matrix ◽

Bile Duct ◽

Biliary Atresia ◽

Bile Ducts ◽

Matrix Protein ◽

Extrahepatic Bile Duct ◽

Fiber Formation ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Extrahepatic Bile Ducts

AbstractEGF-Containing Fibulin Extracellular Matrix Protein 1 (EFEMP1, also called fibulin 3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibro-inflammatory disease of the neonatal extrahepatic bile duct. EFEMP1 is expressed in most tissues and Efemp1 null mice have decreased elastic fibers in visceral fascia; however, in contrast to other short fibulins (fibulins 4 and 5), EFEMP1 does not have a role in the development of large elastic fibers, and its overall function remains unclear. We demonstrated that EFEMP1 is expressed in the submucosa of both neonatal and adult mouse and human extrahepatic bile ducts and that, in adult Efemp1+/- mice, elastin organization into fibers is decreased. We used pressure myography, a technique developed to study the mechanics of the vasculature, to show that Efemp1+/- extrahepatic bile ducts are more compliant to luminal pressure, leading to increased circumferential stretch. We conclude that EFEMP1 has an important role in the formation of elastic fibers and mechanical properties of the extrahepatic bile duct. These data suggest that altered expression of EFEMP1 in the extrahepatic bile duct leads to an abnormal response to mechanical stress such as obstruction, potentially explaining the role of EFEMP1 in biliary atresia.

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