Fibronectins, Their Fibrillogenesis, and In Vivo Functions

Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Cold Spring Harbor perspectives in biology (Impact Factor: 8.68). 05/2011; 3(7). DOI: 10.1101/cshperspect.a005041
Source: PubMed


Fibronectin (FN) is a multidomain protein with the ability to bind simultaneously to cell surface receptors, collagen, proteoglycans, and other FN molecules. Many of these domains and interactions are also involved in the assembly of FN dimers into a multimeric fibrillar matrix. When, where, and how FN binds to its various partners must be controlled and coordinated during fibrillogenesis. Steps in the process of FN fibrillogenesis including FN self-association, receptor activities, and intracellular pathways have been under intense investigation for years. In this review, the domain organization of FN including the extra domains and variable region that are controlled by alternative splicing are described. We discuss how FN-FN and cell-FN interactions play essential roles in the initiation and progression of matrix assembly using complementary results from cell culture and embryonic model systems that have enhanced our understanding of this process.

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Available from: Jean E Schwarzbauer
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    • "Chemical and mechanical signals emanating from the fibronectin matrix are transduced through the integrin family of adhesion receptors. Matrix-based signals integrate with those from signaling pathways initiated through growth factors, cytokines and intercellular adhesion receptors (Schwarzbauer and DeSimone, 2011). It is through these matrix-based signaling networks that fibronectin exerts its influence over nearly all aspects of endothelial cell biology (Astrof and Hynes, 2009; Malinin et al., 2012). "
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    ABSTRACT: The fibronectin matrix plays a critical role in the regulation of angiogenesis during development, tissue repair and disease pathogenesis. Earlier work has identified a fibronectin-derived homophilic binding peptide, anastellin, as an effective inhibitor of angiogenesis; however its mechanism of action is not well understood. In the present study, we demonstrate that anastellin selectively inhibits microvessel cell signaling in response to VEGF165 but not VEGF121 by preventing the assembly of the VEGF receptor/Neuropilin-1 complex. Anastellin treatment resulted in the inactivation of α5β1 integrins but was not accompanied by a change in either adhesion complexes or adhesion based signaling. Integrin inactivation was associated with a masking of the fibronectin synergy site within the extracellular matrix, indicating that α5β1 inactivation resulted from a decrease in available ligand. These data demonstrate that anastellin influences the microvessel cell response to growth factors by controlling the repertoire of ligated integrins and point to anastellin as an effective regulator of fibronectin matrix organization. These studies further suggest that homophilic fibronectin binding peptides may have novel applications to the field of tissue regeneration as tools to regulate neovascularization.
    Preview · Article · Jun 2014 · Journal of Cell Science
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    • "Modification with fibronectin can be used to study effects of cell attachment. Fibronectin (Fn) is an extracellular glycoprotein that binds both cell integrins and other ECM molecules, and plays a major role in cell adhesion, growth and differentiation [42]. This glycoprotein is also important for neural development by promoting cell survival, migration, neurite outgrowth and synapse formation [43]. "
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    ABSTRACT: Biomaterial-supported culture methods, allowing for directed three-dimensional differentiation of stem cells are an alternative to canonical two-dimensional cell cultures. In this paper, we evaluate the suitability of alginate for three-dimensional cultures to enhance differentiation of mouse embryonic stem cells (mESCs) towards neural lineages. We tested whether encapsulation of mESCs within alginate beads could support and/or enhance neural differentiation with respect to two-dimensional cultures. We encapsulated cells in beads of alginate with or without modification by fibronectin (Fn) or hyaluronic acid (HA). Gene expression analysis showed that cells grown in alginate and alginate-HA present increased differentiation toward neural lineages with respect to the two-dimensional control and to Fn group. Immunocytochemistry analyses confirmed these results, further showing terminal differentiation of neurons as seen by the expression of synaptic markers and markers of different neuronal subtypes. Our data show that alginate, alone or modified, is a suitable biomaterial to promote in vitro differentiation of pluripotent cells toward neural fates.
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    • "Normally it is integrins (cell membrane protein) that connect cells, including prostatic epithelial cells, to the ECM by binding to fibronectin already present in the matrix 47. This interaction is required for proper assembly of fibronectin in the matrix, something that is very important for ECM organization and stability 48, 49. Cancer typically involves an epithelial to mesenchymal transition (EMT), whereby malignant cells can now break loose of their defined position within the microenvironment. "
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    ABSTRACT: Globally, Prostate cancer (PCa) is the most frequently occurring non-cutaneous cancer, and is the second highest cause of cancer mortality in men. Serum prostate specific antigen (PSA) has been the standard in PCa screening since its approval by the American Food & Drug Administration (FDA) in 1994. Currently, PSA is used as an indicator for PCa - patients with a serum PSA level above 4ng/mL will often undergo prostate biopsy to confirm cancer. Unfortunately fewer than ~30% of these men will biopsy positive for cancer, meaning that the majority of men undergo invasive biopsy with little benefit. Despite PSA's notoriously poor specificity (33%), there is still a significant lack of credible alternatives. Therefore an ideal biomarker that can specifically detect PCa at an early stage is urgently required. The aim of this study was to investigate the potential of using deregulation of urinary proteins in order to detect Prostate Cancer (PCa) among Benign Prostatic Hyperplasia (BPH). To identify the protein signatures specific for PCa, protein expression profiling of 8 PCa patients, 12 BPH patients and 10 healthy males was carried out using LC-MS/MS. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This approach revealed that significant the down-regulation of Fibronectin and TP53INP2 was a characteristic event among PCa patients. Fibronectin mRNA down-regulation, was identified as offering improved specificity (50%) over PSA, albeit with a slightly lower although still acceptable sensitivity (75%) for detecting PCa. As for TP53INP2 on the other hand, its down-regulation was moderately sensitive (75%), identifying many patients with PCa, but was entirely non-specific (7%), designating many of the benign samples as malignant and being unable to accurately identify more than one negative.
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