Binding of soluble fibronectin to integrin α5β1 – link to focal adhesion redistribution and contractile shape

Huveneers, Stephan; Truong, Hoa; Faessler, R.; Sonnenberg, Arnoud; Danen, Erik H.J.

doi:10.1242/jcs.033001

Cited by 132 publications

(104 citation statements)

References 47 publications

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“…Interestingly, a connection between Rab21, integrins and actomyosin regulation has been reported during cytokinesis (Pellinen et al, , 2008. This is probably through the activation of Rho-ROCK function as ligand-bound integrin a5 can signal to RhoGEFs and thereby increase Rho activity (Ren et al, 1999;Dubash et al, 2007;Huveneers et al, 2008). Integrin a5 has also been implicated in collagen gel contraction in other fibroblast types (Liu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion

2009

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BACKGROUND: Carcinoma-associated fibroblasts (CAFs) can promote the progression of tumours in many ways. They can remodel the extracellular matrix to generate an environment that enables the invasion of cancer cells. We hypothesised that compounds that prevent matrix remodelling by CAFs would block their ability to promote carcinoma cell invasion. METHODS: We designed a screen for compounds that interfere with CAF-promoted matrix remodelling. Hits from this screen were investigated in organotypic invasion models of squamous cell carcinoma (SCC). RESULTS: We find that lovastatin and simvastatin reduce matrix remodelling by fibroblasts and thereby reduce SCC invasion. This class of compounds exert their effects partly through disrupting the function of Rab proteins, and we show a new role for Rab21 in promoting cancer cell invasion promoted by CAFs. CONCLUSIONS: Rab21 is required for CAFs to promote the invasion of cancer cells. It enables the accumulation of integrin a5 at the plasma membrane and subsequent force-mediated matrix remodelling.

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Section: Discussionmentioning

confidence: 99%

A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion

2009

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“…Analysis of FN Matrix Assembly via Fluorescence StainingFibronectin fibril formation was measured by the assembly of exogenously added biotin-labeled FN by a modification of Huveneers et al (15). 6 ϫ 10 4 cells/well of wild type, syndecan-4 null, ␤1 integrin null, EA5, and EA5/␣5 cells were seeded onto FN or TG-FN in 8-well glass chamber slides.…”

Section: Establishment Of the Tg2-transfected Mef (Tg2-mef) Cell Linementioning

confidence: 99%

“…A prerequisite for fibronectin fibril formation is the formation of focal adhesions (15). We therefore investigated focal adhesion formation in MEF cells treated with RAD or RGD peptides when plated on FN or TG-FN matrices.…”

Section: Rgd-independent Tg-fn-mediated Cell Adhesion Can Influence Fmentioning

confidence: 99%

“…Our hypothesis that ␣5 integrin is also the major companion of ␤1 integrin in mediating RGD-independent cell adhesion on TG-FN was first tested by using ␣5 integrin knock-out EA5 embryo cells and control EA5/␣5 cells (EA5 transfected back with ␣5 integrin) (supplemental Fig. 1B) (15). Without ␣5 integrin, the EA5 cells adhered poorly compared with the control cells, and the adhesive response of the knock-out cells was much more susceptible to RGD peptide than that of its control cells (Fig.…”

Section: ␣5␤1 Integrin Is Required For Tg-fn To Exert Its Function Inmentioning

confidence: 99%

“…A further role of another syndecan family member, syndecan-2, was demonstrated as a downstream molecule in the syndecan-4 signaling pathway (14), although the intermediate protein(s) mediating this signaling have not been characterized. Apart from supporting the cell adhesion process, cell surface receptors are also involved in the assembly of inactive soluble fibronectin dimers into insoluble fibronectin fibrils to further support the cell adhesion process, among which ␣5␤1 integrins are proba-bly the most efficient regulators and the most widely studied (15). Cell contractility mediated via the actin-myosin cytoskeleton and stimulated via activation of GTPase Rho (16) is needed to stretch the soluble fibronectin dimers, making the cell surface receptor binding sites available.…”

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confidence: 99%

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RGD-independent Cell Adhesion via a Tissue Transglutaminase-Fibronectin Matrix Promotes Fibronectin Fibril Deposition and Requires Syndecan-4/2 and α5β1 Integrin Co-signaling

Wang

Collighan

Gross

et al. 2010

Journal of Biological Chemistry

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Fibronectin (FN) deposition mediated by fibroblasts is an important process in matrix remodeling and wound healing. By monitoring the deposition of soluble biotinylated FN, weshow that the stress-induced TG-FN matrix, a matrix complex of tissue transglutaminase (TG2) with its high affinity binding partner FN, can increase both exogenous and cellular FN deposition and also restore it when cell adhesion is interrupted via the presence of RGD-containing peptides. This mechanism does not require the transamidase activity of TG2 but is activated through an RGD-independent adhesion process requiring a heterocomplex of TG2 and FN and is mediated by a syndecan-4 and ␤1 integrin co-signaling pathway. By using ␣5 null cells, ␤1 integrin functional blocking antibody, and a ␣5␤1 integrin targeting peptide A5-1, we demonstrate that the ␣5 and ␤1 integrins are essential for TG-FN to compensate RGD-induced loss of cell adhesion and FN deposition. The importance of syndecan-2 in this process was shown using targeting siRNAs, which abolished the compensation effect of TG-FN on the RGD-induced loss of cell adhesion, resulting in disruption of actin skeleton formation and FN deposition. Unlike syndecan-4, syndecan-2 does not interact directly with TG2 but acts as a downstream effector in regulating actin cytoskeleton organization through the ROCK pathway. We demonstrate that PKC␣ is likely to be the important link between syndecan-4 and syndecan-2 signaling and that TG2 is the functional component of the TG-FN heterocomplex in mediating cell adhesion via its direct interaction with heparan sulfate chains. Fibronectin (FN)3 mediates the cell adhesion process by interacting with cell surface receptors through its different cell binding sites. It is essential to embryogenesis and found associated with the extracellular matrix in large quantities during wound healing and angiogenesis. The amino acid sequence Arg-Gly-Asp (RGD) found within FN and many other matrix proteins is the most widely occurring cell-adhesive motif (1). It is the most important recognition site for about half of all known integrins, such as ␣5␤1, ␣V␤1, ␣V␤3, and ␣V␤5 (2). However, this cell adhesion process can easily be inhibited by the presence of competitive peptides containing the RGD sequence, often leading to apoptosis (anoikis) (3, 4). Such peptides are commonly released during matrix remodeling, a process that is essential to both wound healing and angiogenesis (5-7). Of the integrins, ␣5␤1 integrin is probably the major cell surface integrin that interacts with the RGDcell binding site on FN, initiating the cell adhesion process (8), whereas the binding of ␣v␤3 integrin to the RGD domain can also support cell adhesion on FN (9). In addition to the RGDcell binding domains, the heparin binding sites within FN have also been reported to be involved in cell adhesion because, although cell binding to the RGD-cell binding domains of FN can initiate the cell adhesion process, it is not sufficient to fully support actin cytoskeleton formation, an observation tha...

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Electrical Control of Protein Conformation

et al. 2012

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Conducting polymer devices that enable precise control of fibronectin conformation over macroscopic areas are reported. Single conformations as well as conformation gradients are achieved by applying an appropriate potential. These surfaces remain biologically relevant and support cell culture; hence, they may serve as a model to understand and control cell-surface interactions, with applications in basic research, medical diagnostics, and tissue engineering.

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Binding of soluble fibronectin to integrin α5β1 – link to focal adhesion redistribution and contractile shape

Cited by 132 publications

References 47 publications

A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion

A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion

RGD-independent Cell Adhesion via a Tissue Transglutaminase-Fibronectin Matrix Promotes Fibronectin Fibril Deposition and Requires Syndecan-4/2 and α5β1 Integrin Co-signaling

Electrical Control of Protein Conformation

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