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Fibronectin

Fibronectin is a large, multidomain glycoprotein that serves as a key structural component of the extracellular matrix (ECM) and is also present in soluble form in blood plasma, where it facilitates cell adhesion, migration, and tissue organization through binding to integrins and other ECM molecules.^[1] Composed of two nearly identical polypeptide chains, each approximately 230–270 kDa, linked by disulfide bonds at their C-termini, fibronectin exhibits a modular structure featuring 12 type I, 2 type II, and 15–17 type III repeating domains that enable its diverse interactions.^[1] It exists in multiple isoforms generated by alternative splicing, including variants with extra type III domains (EDA and EDB) that are particularly prominent in cellular fibronectin produced by fibroblasts and other mesenchymal cells, as opposed to the plasma form synthesized primarily by hepatocytes.^[2] In its fibrillar form, fibronectin is assembled by cells into insoluble, viscoelastic networks within the ECM through a process called fibrillogenesis, which involves integrin-mediated mechanical tension that unfolds domains to expose cryptic binding sites for self-association and interactions with collagens, fibrin, and over 40 growth factors such as TGF-β and VEGF.^[1] This assembly is essential for ECM maturation and mechanotransduction, allowing cells to sense and respond to mechanical cues in their environment.^[1] Plasma fibronectin, circulating at concentrations of 300–400 μg/mL, differs from cellular fibronectin by lacking EDA and EDB domains and plays a distinct role in early hemostasis by stabilizing fibrin clots during initial wound response.^[2] Physiologically, fibronectin is indispensable for embryonic development, where it supports processes like gastrulation and branching morphogenesis, as evidenced by severe defects in fibronectin-null mice.^[2] In adult tissues, it promotes wound healing by guiding fibroblast migration, angiogenesis, and ECM remodeling, with EDA-containing isoforms enhancing cell motility and proliferation at injury sites.^[1] Dysregulation of fibronectin contributes to pathological conditions, including fibrosis—where excessive fibril deposition stiffens tissues in organs like the lungs and kidneys—and cancer progression, as oncofetal isoforms facilitate tumor invasion and metastasis.^[2]

Structure and Isoforms

Primary Structure

Fibronectin is a high-molecular-weight glycoprotein that exists as a dimer, with each subunit ranging from approximately 220 to 250 kDa, resulting in a total molecular mass of 440 to 500 kDa for the intact molecule.^[3] The two subunits are covalently linked by two disulfide bonds near their C-termini, forming a structure that is flexible and elongated under physiological conditions. This dimeric organization is essential for its role in extracellular matrix assembly, though the primary structure itself dictates the modular blueprint independent of assembly dynamics. The primary structure of fibronectin is characterized by a modular architecture consisting of repeating domains: approximately 12 type I modules, 2 type II modules, and 15 to 17 type III modules, which together comprise about 90% of the polypeptide sequence.^[3] Type I modules, each about 40 amino acids long, feature two antiparallel β-sheets stabilized by three intramolecular disulfide bonds and are distributed at both the N- and C-termini, with the first five forming the N-terminal assembly domain that contributes to interactions with collagen and fibrin.^[4] Type II modules, roughly 60 amino acids each, adopt a compact globular fold with two β-sheets and three disulfide bonds, facilitating gelatin and collagen binding.^[5] In contrast, type III modules, around 90 amino acids apiece, form rod-like β-sandwich structures composed of seven β-strands without intramolecular disulfide bonds, enabling mechanical unfolding under tensile forces to expose cryptic binding sites for integrins.^[6] This modular repetition allows for a "beads-on-a-string" linear arrangement, with inter-module linkers providing flexibility. Biophysically, fibronectin exhibits distinct solubility properties depending on its form: the plasma variant is highly soluble at concentrations up to 300–400 μg/mL in circulation, while the matrix-associated form becomes insoluble through polymerization into fibrils. The N-terminal 70-kDa fragment, comprising the first five type I modules, plays a pivotal role in initiating fibril assembly by self-associating and binding to other fibronectin domains.^[7] These properties arise from the intrinsic hydrophilicity of the soluble dimer and the exposure of hydrophobic sites during conformational changes in the matrix context. The modular domains of fibronectin demonstrate strong evolutionary conservation across metazoans, with type III modules particularly preserved in sequence and fold from invertebrates to mammals, underscoring their ancient origin in extracellular matrix evolution. Type I and II modules also show conservation in vertebrates, reflecting selective pressure for matrix-binding functionalities.^[8]

Isoforms and Splicing Variants

Fibronectin, a modular glycoprotein encoded by a single gene, undergoes extensive alternative splicing to produce multiple isoforms that exhibit tissue-specific expression and functional diversity. The primary sites of alternative splicing occur within three regions: the extra type III domain A (EDA, also known as EIIIA), extra type III domain B (EDB, or EIIIB), and the connecting segment-1 (CS, also referred to as the IIICS or V region). These splicing events allow for the inclusion or exclusion of specific exons, generating up to 20 distinct isoforms in humans, with variations in domain composition that influence protein solubility, matrix incorporation, and interactions with cells.^[9]^[10] The EDA and EDB exons each encode a complete type III repeat and are typically excluded in plasma fibronectin, the soluble form predominantly synthesized by hepatocytes in the liver and circulating at concentrations of approximately 300–400 μg/mL in human blood. In contrast, cellular fibronectin isoforms, produced mainly by fibroblasts and other mesenchymal cells, often include EDA and/or EDB, rendering them insoluble and prone to incorporation into the extracellular matrix. The CS region is more complex, undergoing variable splicing to produce isoforms such as V120 (full inclusion), V95 (partial inclusion with a 25-amino-acid deletion), and V0 (complete exclusion), which further diversifies the protein's adhesive properties. Plasma fibronectin generally lacks EDA and EDB but may include partial CS variants, while cellular forms show greater heterogeneity in all three sites.^[11]^[12]^[13] Tissue distribution of these isoforms is tightly regulated and reflects developmental and physiological needs. EDA and EDB are minimally expressed in healthy adult tissues but become prominently included during embryogenesis, wound healing, and tumorigenesis, where they can constitute up to 90% of total fibronectin in affected areas. For instance, EDA+ isoforms predominate in embryonic tissues and healing wounds, while EDB+ forms are enriched in vascularized embryonic structures and tumor stroma. The plasma isoform predominates in circulation and quiescent tissues, whereas cellular isoforms with EDA/EDB are fibroblast-derived and matrix-associated in dynamic environments like embryos and tumors.^[14]^[15]^[9] Functionally, the inclusion of EDA and EDB domains enhances fibrillogenesis and matrix stability, promoting stronger interactions with integrins such as α5β1 and αvβ3, which in turn amplify cell adhesion, spreading, and signaling pathways like focal adhesion kinase (FAK) activation. These extra domains also modulate cell proliferation and survival, with EDA+ fibronectin supporting migratory phenotypes in fibroblasts and endothelial cells. The variable CS region, particularly the CS1 peptide in V120 and V95 isoforms, plays a key role in cell motility by binding to integrins like α4β1, facilitating leukocyte migration and tumor cell invasion without significantly affecting matrix assembly. In contrast, the V0 isoform reduces these adhesive interactions, altering cellular responses to the matrix.^[16]^[17]^[13] Recent studies have elucidated the role of the EDB isoform in tumor angiogenesis, highlighting its pro-vascularization effects through interactions with vascular endothelial growth factor (VEGF). For example, FN-EDB upregulates VEGF expression and matrix metalloproteinases in the tumor microenvironment, enhancing endothelial cell proliferation and vessel formation, which correlates with poor prognosis in various cancers. A 2025 review emphasized FN-EDB's potential as a therapeutic target, as its blockade disrupts angiogenesis without affecting normal vasculature. These findings build on earlier work showing EDB's specificity to angiogenic tissues, underscoring splicing's role in pathological adaptation.^[18]^[19]^[20]

Biological Functions

Cell Adhesion and Migration

Fibronectin plays a central role in mediating cell adhesion to the extracellular matrix through specific interactions with integrin receptors on the cell surface. The primary binding site for these interactions is the Arg-Gly-Asp (RGD) motif located within the tenth type III module (FNIII10) of the fibronectin molecule, which serves as the key recognition sequence for integrins such as α5β1 and αvβ3.^[21] This motif enables direct attachment of cells like fibroblasts and endothelial cells to fibronectin substrates, facilitating stable anchorage during tissue organization.^[22] Adhesion specificity and affinity are further enhanced by a synergy region in the adjacent ninth type III module (FNIII9), containing the Pro-His-Ser-Arg-Asn (PHSRN) sequence, which cooperates with the RGD site to promote high-avidity binding, particularly to α5β1 integrin.^[22] Mutations or disruptions in this synergy site significantly reduce cell attachment efficiency on fibronectin-coated surfaces, underscoring its importance in selective integrin engagement. Beyond direct cell adhesion, fibronectin's N-terminal domains contribute to opsonization by binding to bacterial surfaces and cellular debris, thereby promoting their recognition and engulfment by phagocytic cells such as monocytes and macrophages through opsonic bridging. This process enhances immune clearance, as demonstrated by increased phagocytosis rates of fibronectin-coated particles compared to uncoated ones in vitro. In the context of cell spreading and motility, fibronectin supports the formation of focal adhesions—dynamic protein complexes that link the actin cytoskeleton to the extracellular matrix—by allowing cells to exert traction forces that unfold fibronectin and expose cryptic binding sites within its modules. These forces, generated through actomyosin contraction, stabilize adhesions and enable cell protrusion, contributing to morphological changes like spreading on fibronectin matrices. Experimental studies using fibronectin-coated glass or plastic surfaces have shown that adherent cells, such as fibroblasts, rapidly extend lamellipodia—broad, actin-rich protrusions—at the leading edge, promoting directed migration with persistence indices up to 0.8 over several hours, far exceeding random movement on non-adhesive substrates.^[23] These in vitro assays highlight fibronectin's role in guiding haptotactic migration, where cells preferentially move toward higher fibronectin densities.

Signaling Pathways and Differentiation

Fibronectin engagement with integrins, particularly α5β1, initiates intracellular signaling cascades that regulate cell proliferation, survival, and cytoskeletal dynamics. Upon binding, integrins cluster at focal adhesions, recruiting and activating focal adhesion kinase (FAK), which autophosphorylates at tyrosine 397 to create a docking site for Src-family kinases.^[24] Src activation further phosphorylates FAK and associated proteins, leading to the recruitment of adapter molecules like paxillin and talin.^[24] This complex activates Rho GTPases, such as RhoA, which promote actin stress fiber formation and focal adhesion maturation.^[25] Downstream, these events converge on the MAPK/ERK pathway to drive gene expression for cell proliferation and the PI3K/Akt pathway to enhance survival by inhibiting apoptosis.^[26] The extra domain A (EDA)-containing isoform of fibronectin plays a specialized role in cell differentiation, particularly promoting myofibroblast differentiation during tissue remodeling. EDA-fibronectin binds to Toll-like receptor 4 (TLR4) on fibroblasts, triggering NF-κB activation and the expression of profibrotic genes such as collagen I and α-smooth muscle actin.^[27] This signaling is cooperative with integrin α4β1, which recognizes the EDA domain and facilitates a biphasic response: an early wave of inflammatory gene induction at 2 hours and a later profibrotic phase at 24 hours.^[28] EDA engagement thus shifts fibroblasts toward a contractile, matrix-producing phenotype essential for developmental processes.^[28] Fibronectin also participates in cross-talk with growth factor pathways to influence epithelial-mesenchymal transition (EMT), a process involving loss of epithelial polarity and gain of migratory traits. Through integrin-mediated adhesion, fibronectin enhances TGF-β signaling by stabilizing Smad complexes and upregulating TGF-β receptor expression, thereby amplifying EMT transcription factors like Snail and Twist.^[29] Concurrently, fibronectin modulates Wnt/β-catenin signaling by facilitating β-catenin stabilization and nuclear translocation, which synergizes with TGF-β to sustain EMT gene programs.^[30] This integration allows fibronectin to fine-tune cellular responses to microenvironmental cues during differentiation.^[31] Quantitative aspects of these interactions underscore their mechanosensitivity. The binding affinity of α5β1 integrin to the RGD motif in fibronectin typically ranges from 10 to 100 nM, with activated states achieving sub-nanomolar dissociation constants (e.g., Kd ≈ 1.7 nM for the fibronectin type III9-10 modules).^[32] Signaling thresholds are force-dependent; integrin unfolding and downstream activation, such as talin-mediated reinforcement, occur above ~2-5 pN per bond, while higher loads (~50-100 pN) trigger clutch slippage and pathway modulation.^[33] These parameters ensure that fibronectin signaling scales with matrix stiffness and tension.^[34]

Extracellular Matrix Dynamics

Synthesis and Secretion

The FN1 gene, which encodes fibronectin, is located on the long arm of human chromosome 2 at the 2q35 band.^[35] Transcription of FN1 is regulated by promoters that respond to environmental cues, including cytokines such as interleukin-1β (IL-1β), which upregulates expression during inflammatory conditions to enhance fibronectin production.^[36] The liver, particularly hepatocytes, serves as the primary site of synthesis for the soluble plasma form of fibronectin, which circulates at concentrations of approximately 300–400 μg/mL.^[2] This hepatic production ensures a steady supply for systemic functions, distinct from the cellular fibronectin assembled locally by fibroblasts and other cell types. Biosynthesis of fibronectin begins with translation on ribosomes associated with the endoplasmic reticulum (ER), where co-translational modifications occur. These include N-linked glycosylation at asparagine residues and O-linked glycosylation at serine or threonine residues, collectively adding about 8% carbohydrate by mass to the mature protein, which influences its stability and interactions.^[37] Within the ER, individual fibronectin polypeptides form dimers linked by disulfide bonds near their C-termini, a critical step for the protein's dimeric structure in both plasma and cellular forms.^[12] Alternative splicing variants, such as those including extra type III domains, can influence the efficiency of these biosynthetic processes, though the core dimerization mechanism remains conserved.^[38] Following processing in the ER and Golgi apparatus, fibronectin is packaged into vesicles for secretion via exocytosis, a process that delivers the dimer to the extracellular space.^[38] Secreted fibronectin initially remains soluble but rapidly associates with the cell surface through interactions with integrins, priming it for incorporation into the extracellular matrix.^[2] This secretion is tightly controlled to match cellular demands. Regulation of fibronectin synthesis involves adaptive responses to cellular stress, notably hypoxia, where hypoxia-inducible factor 1α (HIF-1α) activates transcriptional feedback loops that increase FN1 expression and subsequent protein production.^[39] For example, in hypoxic environments, HIF-1α signaling enhances fibronectin levels via pathways like PI3K/Akt, supporting cell survival and migration without altering baseline dimerization or glycosylation.^[39] Such mechanisms ensure responsive production in dynamic physiological contexts.

Fibrillogenesis and Matrix Assembly

Fibrillogenesis is the process by which soluble fibronectin (FN) dimers polymerize into insoluble fibrillar structures within the extracellular matrix (ECM), forming a scaffold essential for tissue architecture. This cell-dependent assembly transforms compact, soluble FN into extended fibrils that can reach lengths of several microns, driven by mechanical forces and molecular interactions. The process requires FN binding to cell surfaces, followed by conformational changes that expose binding sites for intermolecular associations.^[1] Initiation of fibrillogenesis begins with the self-association of the N-terminal 70-kDa domain (comprising modules I1-9), which binds to cell-surface receptors such as integrins (e.g., α5β1) and syndecans to anchor FN dimers. This anchoring occurs primarily through the RGD motif in the III10 module and synergy sites in III9, enabling integrin clustering and linkage to the actin cytoskeleton, which generates tensile forces necessary for assembly. Syndecans, particularly syndecan-1 and -2, facilitate initial FN deposition by promoting focal adhesion formation and modulating integrin activation, thereby nucleating fibril formation at cell-ECM interfaces.^[7] Elongation proceeds through cell-generated tensile forces that induce partial unfolding of type III modules, such as III1-3 and III12-14, exposing cryptic self-binding sites like those in III1 and the HepII domain (modules I13-15). This unfolding allows β-strand exchange between FN molecules, promoting end-to-end and lateral associations that extend fibrils into quaternary structures. The resulting fibrils exhibit a periodic alignment of FN dimers, with unfolding primarily in the III1 domain facilitating rapid elongation under mechanical tension from actomyosin contractility.^[40]^[1] Cross-linking integrates FN fibrils with other ECM components, enhancing network stability. The type I modules (I6-9 and I1-2) mediate binding to collagen, while modules I10-12 interact with fibrin, incorporating FN into provisional matrices during wound healing. Transglutaminase enzymes, such as factor XIIIa, further stabilize these networks by forming covalent cross-links between FN molecules and associated proteins like collagen and fibrin, converting soluble multimers into insoluble fibrils resistant to extraction.^[41]^[1] The kinetics of fibrillogenesis are time-dependent, typically spanning hours to days, with initial deposition forming small multimers that mature into thick fibrils under sustained tension. Factors such as pH and ionic strength modulate assembly; elevated pH or high ionic strength promotes FN extension and thicker fibrils by altering conformational states, while co-factors like CD93 enhance β1 integrin activation to accelerate initiation during angiogenesis. These dynamics ensure regulated ECM formation, with fibril thickness varying from nanometers to hundreds of nanometers based on environmental cues. Recent studies (as of 2025) highlight fibronectin fibrillogenesis's role in driving three-dimensional neovessel formation and enhancing anti-tumor responses through α5β1 integrin-mediated matrix remodeling.^[7]^[42]^[43]

Physiological Roles

In Embryonic Development and Homeostasis

Fibronectin was first identified in the 1970s as the large external transformation-sensitive protein (LETS), a surface glycoprotein prominent on embryonic fibroblasts and lost in transformed cells, highlighting its early recognition in developmental contexts.^[44] This discovery laid the groundwork for understanding fibronectin's role in cellular adhesion and tissue organization during embryogenesis. During gastrulation and morphogenesis, fibronectin plays a pivotal role in guiding mesoderm cell migration through interactions with integrin receptors, particularly α5β1, which facilitate polarized cell protrusions and mediolateral intercalation essential for embryonic axis elongation.^[45] In fibronectin-null mice, embryos implant normally but exhibit lethal defects shortly after, around embryonic day 8.5, due to impaired mesoderm migration, neural tube closure, and vascular development, underscoring fibronectin's indispensability for these processes.^[46] These integrin-fibronectin interactions, briefly referencing adhesion mechanisms from broader cellular contexts, enable the spatiotemporal assembly of extracellular matrix fibrils that direct tissue patterning. In angiogenesis and vasculogenesis, fibronectin supports endothelial cell tube formation and vessel remodeling by providing a scaffold for cell adhesion and migration during embryonic cardiovascular development.^[47] The extra domain A (EDA)-containing isoform of fibronectin contributes to vascular integrity and organogenesis, as evidenced by roles in angiogenesis; severe defects in heart and vascular development occur in fibronectin-null mice, emphasizing isoform-specific contributions to organogenesis.^[47] For tissue homeostasis, fibronectin maintains basement membrane integrity by integrating with other extracellular matrix components, ensuring structural support and regulating cellular behaviors in adult tissues.^[48] It also modulates stem cell niches, such as in skeletal muscle where it influences satellite cell quiescence and activation through integrin-mediated signaling.^[49] Fibronectin turnover is balanced by synthesis from resident cells and degradation primarily by matrix metalloproteinases MMP-2 and MMP-9, which cleave it to prevent excessive accumulation while preserving matrix dynamics for long-term tissue maintenance.^[50]

In Wound Healing and Tissue Repair

In the hemostasis phase of wound healing, plasma fibronectin rapidly extrudes from blood vessels and binds to fibrin within the forming clot, contributing to the assembly of a provisional extracellular matrix that stabilizes the wound site and facilitates initial cell adhesion.^[51] This binding occurs primarily through the N-terminal domains of fibronectin interacting with fibrin polymerization sites, enhancing clot integrity and providing a scaffold for subsequent cellular infiltration.^[52] Additionally, plasma fibronectin acts as a nonimmune opsonin, promoting the phagocytosis of cellular debris and pathogens by macrophages and other immune cells, thereby clearing the wound bed during this early stage.^[53]^[54] During the inflammation and proliferation phases, cellular fibronectin, particularly the extra domain A (EDA)-containing isoform, is upregulated and secreted by fibroblasts and endothelial cells to support granulation tissue formation. The EDA isoform binds to integrins on fibroblasts, promoting their recruitment to the wound site and differentiation into myofibroblasts, which deposit new extracellular matrix components essential for tissue rebuilding.^[55]^[56] This process facilitates angiogenesis and epithelial cell migration across the provisional matrix, with fibronectin's role in cell adhesion further enabling directed fibroblast movement into the injury area. Recent 2025 research has demonstrated that engineered fibronectin variants, such as those fused with platelet factor 4 domains or incorporated into nanofiber scaffolds, enhance fibroblast and keratinocyte migration rates by up to 50% in vitro, offering potential for improved scaffolds in chronic wound therapies.^[57]^[58] In the remodeling phase, fibronectin integrates with newly synthesized collagen type I fibrils, stabilizing the maturing granulation tissue and guiding its alignment to restore mechanical strength. This integration occurs via fibronectin's collagen-binding domains, which template collagen fibrillogenesis and prevent disorganized deposition.^[59] As healing progresses, excess fibronectin is degraded by plasmin and matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, to facilitate scar resolution and tissue maturation, with balanced proteolysis ensuring the extracellular matrix achieves approximately 80% of normal tensile strength.^[60]^[61] Clinically, fibronectin deficiencies or dysfunctional matrix assembly are associated with impaired wound healing in diabetic patients, where hyperglycemia disrupts fibronectin secretion and fibrillogenesis, leading to persistent inflammation and delayed closure.^[62] Topical applications of fibronectin or its mimetics have shown promise in preclinical models, accelerating re-epithelialization by 20-30% in irradiated or full-thickness wounds, and ongoing investigations, including NIH-funded projects on chimeric fibronectin fragments like Chimectin, aim to translate these into human trials for enhanced repair in compromised healing scenarios.^[63]^[64]^[65]

Pathological Roles

In Cancer Progression and Metastasis

In cancer, fibronectin (FN) plays a pivotal role in tumor stroma remodeling by upregulating cellular FN isoforms containing extra domain A (EDA) and extra domain B (EDB), which promote epithelial-mesenchymal transition (EMT) and invasion. EDA-FN, secreted by cancer-associated fibroblasts, enhances tumor cell migration and scattering through integrin αvβ6 and α9β1 signaling, as demonstrated in in vitro studies of head and neck squamous cell carcinoma cells.^[66] Similarly, EDB-FN accumulates in the tumor stroma, fostering matrix stiffness and facilitating EMT via TGF-β pathway activation in various carcinomas, such as prostate cancer.^[67] These isoforms also drive angiogenesis; for instance, EDA-FN upregulates VEGF-C expression in colorectal cancer cells, supporting neovascularization.^[68] In gliomas, EDB-FN serves as a specific marker for tumor angiogenesis, with 2025 studies, including those exploring targeting oncofetal fibronectin in solid tumors, showing its overexpression correlates with poor prognosis and increased vascular density in high-grade malignancies.^[69] FN further facilitates metastasis by contributing to pre-metastatic niche formation through targeted deposition in distant organs. Tumor-derived exosomes from pancreatic and melanoma cells induce FN upregulation in stromal cells of the lung and liver, creating adhesive scaffolds that recruit VEGFR1+ bone marrow-derived cells via α4β1 integrin binding, thereby promoting inflammation and immune suppression. This FN-enriched environment enhances vascular permeability and prepares sites for circulating tumor cell (CTC) seeding. Additionally, FN interactions with CTCs improve survival during circulation; plasma FN protects melanoma and lung cancer cells from cytotoxic effects of inflammatory mediators by facilitating invasion into fibrin clots and subsequent lung metastasis in mouse models.^[70] Therapeutic strategies targeting FN show promise in inhibiting cancer progression, particularly through anti-FN antibodies and RGD mimetics. In breast cancer models like E0771, function-blocking antibodies against integrin α5β1 reduce FN fibril assembly, enhancing CD8+ T cell infiltration and synergizing with PD-L1 checkpoint blockade to achieve complete tumor regressions.^[42] Anti-EDB FN antibody-drug conjugates eliminate tumors in preclinical settings and exhibit enhanced efficacy when combined with immune checkpoint inhibitors in solid tumor xenografts.^[71] RGD mimetics, which disrupt FN-integrin binding, have been tested in clinical trials for melanoma; for example, the αvβ3-targeted antibody Abegrin (etaracizumab) was evaluated in Phase II trials (NCT00072930), showing limited clinical activity when combined with dacarbazine in advanced metastatic melanoma.^[72] Moreover, FN1-FGFR1 gene fusions, identified in 42% of phosphaturic mesenchymal tumors—a rare sarcoma subtype—drive oncogenic signaling and represent actionable targets, with fusion prevalence confirmed in studies from 2015 to 2024.^[73] As a biomarker, FN levels aid in assessing cancer aggressiveness and treatment response. Elevated serum and plasma FN correlates with poor prognosis in non-small cell lung cancer (NSCLC), where higher concentrations reflect increased stromal remodeling and EMT. In prostate cancer, FN-mediated adhesion via β1 and αvβ3 integrins confers resistance to TNF-α-induced apoptosis and chemotherapeutic agents by activating survival pathways like Akt/survivin, though it does not protect against radiotherapy.^[74]^[75]

In Fibrosis, Cardiovascular Diseases, and Other Pathologies

Fibronectin plays a central role in the pathogenesis of fibrosis across multiple organs, where persistent expression of its extra domain A (EDA)-containing isoform promotes the maintenance of myofibroblasts, contractile cells responsible for excessive extracellular matrix (ECM) deposition. In liver and kidney fibrosis, EDA-fibronectin interacts with α4β1 integrin on fibroblasts, enhancing their differentiation into myofibroblasts and sustaining a profibrotic phenotype that resists apoptosis and resolution. This persistent EDA expression is particularly evident in chronic models, where it drives ongoing ECM accumulation and scar formation, contributing to organ dysfunction. Similarly, in idiopathic pulmonary fibrosis (IPF), dysregulation of matrix metalloproteinases (MMPs), such as MMP-9 and MMP-7, impairs the degradation of fibronectin-rich ECM, leading to unbalanced remodeling and progressive lung stiffness as highlighted in recent mechanistic reviews. In cardiovascular diseases, fibronectin contributes to both plaque stability and adverse remodeling processes. During atherosclerosis, EDA-fibronectin stabilizes plaques by modulating smooth muscle cell (SMC) phenotypes, reducing SMC apoptosis and promoting collagen production within the fibrous cap, which helps prevent rupture in advanced lesions. Post-myocardial infarction (MI), fibronectin isoforms, including EDA variants, accumulate in the infarct zone to support initial reparative ECM assembly; however, excessive or dysregulated deposition exacerbates ventricular remodeling, leading to fibrosis and impaired cardiac function. In hypertension, transforming growth factor-β (TGF-β) induces elevated fibronectin expression in vascular smooth muscle cells, promoting ECM hypertrophy and vascular stiffness that perpetuate elevated blood pressure. Beyond fibrotic and cardiovascular contexts, fibronectin influences other pathologies through fragment-mediated inflammation and impaired immune responses. In arthritis, particularly osteoarthritis and rheumatoid arthritis, proteolytic fragments of synovial fibronectin, such as the 45-kDa fragment, act as pro-inflammatory signals by binding integrins like α5β1 on synovial fibroblasts and chondrocytes, inducing cytokine release (e.g., IL-6, MMP-13) and cartilage degradation. Regarding bacterial infections, dysregulated fibronectin in pathological states can impair opsonization, as fibronectin normally bridges bacteria to phagocytes via its binding to bacterial fibronectin-binding proteins and host integrins; however, in conditions like chronic inflammation or ECM alterations, this process fails, increasing susceptibility to pathogens such as Staphylococcus aureus by favoring bacterial adhesion over clearance. Therapeutic strategies targeting fibronectin hold promise for mitigating these pathologies, with anti-fibrotic agents like pirfenidone demonstrating efficacy in reducing fibronectin deposition. Pirfenidone inhibits TGF-β-driven fibronectin synthesis and myofibroblast differentiation, thereby attenuating ECM accumulation in IPF and other fibrotic models, as evidenced by decreased fibronectin levels in treated fibroblasts and improved tissue outcomes in preclinical studies. Ongoing research explores fibronectin-specific inhibitors to enhance plaque stability in atherosclerosis or modulate fragment activity in arthritis, aiming to restore balanced ECM dynamics without disrupting physiological repair.

Genetic and Regulatory Aspects

Genetic Variations and Polymorphisms

The FN1 gene, located on chromosome 2q35, spans approximately 75 kb and consists of 47 exons that encode the modular structure of fibronectin, including type I, II, and III repeats essential for its multifunctional roles.^[76] These exons facilitate alternative splicing, contributing to isoform diversity, though sequence variations primarily occur as single nucleotide polymorphisms (SNPs) or rare mutations that influence expression or function. Common SNPs, such as rs1250259 (leading to a L15Q substitution in the signal peptide), alter fibronectin processing and secretion, thereby modulating plasma levels and associating with cardiovascular traits. Rare loss-of-function variants in FN1 provide protection against Alzheimer's disease, particularly in APOEε4 carriers. A 2024 study identified the missense variant rs140926439 (p.Gly357Glu) in exon 10, which reduces AD risk (OR=0.29, 95% CI 0.11-0.78) and delays onset by about 3.4 years in homozygous APOEε4 individuals by limiting fibronectin deposition at the blood-brain barrier, thereby enhancing glymphatic clearance and reducing amyloid-β accumulation.^[77] Similarly, the rare variant rs116558455 was enriched in unaffected elderly APOEε4 homozygotes, supporting a protective role through impaired fibronectin matrix assembly that mitigates neurovascular pathology.^[78] FN1 variants also confer disease susceptibility in other contexts. Intronic polymorphisms, including rs56380797 and rs35343655, increase risk for cerebral vein thrombosis by potentially disrupting regulatory elements and fibronectin-mediated hemostasis, with higher frequencies observed in affected cohorts. In cancer, the SNP rs6707530 (GG genotype) correlates with elevated FN1 expression, promoting invasive tumor morphology in colorectal cancer by facilitating extracellular matrix remodeling and cell migration.^[79] Rare heterozygous mutations, such as missense changes in type III repeats (e.g., p.Trp1925Arg, rs137854486), underlie glomerulopathy with fibronectin deposits, causing dominant-negative effects that lead to glomerular fibronectin accumulation, proteinuria, and progressive renal failure in up to 40% of familial cases.^[80] Allele frequencies of FN1 variants exhibit ethnic variation, influencing population-specific disease risks. For instance, the protective rs140926439 shows higher prevalence in Caribbean Hispanic cohorts (up to 3.3%) compared to non-Hispanic Whites (absent or <1% in gnomAD European data), potentially contributing to lower AD burden in certain groups, while other risk alleles like those in cardiovascular loci vary similarly across ancestries.^[78]

Protein Interactions and Post-Translational Modifications

Fibronectin engages in multiple protein interactions that are essential for its integration into the extracellular matrix and regulation of cellular processes. It binds to various collagens, including types I through V, primarily through its type I modules, facilitating matrix assembly and stability.^[81] Additionally, fibronectin interacts with heparin and other glycosaminoglycans via its type II and III modules (specifically modules 12-14), which modulates its conformation and binding affinity to other matrix components.^[81] The N-terminal domain of fibronectin also binds fibrin, promoting the incorporation of fibronectin into fibrin clots during hemostasis and early wound healing.^[81] Furthermore, co-receptors such as CD93 enhance fibronectin's fibrillogenesis by activating β1 integrins, thereby supporting matrix organization during angiogenesis.^[82] Post-translational modifications significantly influence fibronectin's solubility, stability, and bioactivity. Phosphorylation of fibronectin, for instance, can occur at specific serine residues and alters its interaction with cells; controlled phosphorylation by kinases like casein kinase II enhances cell attachment and traction forces on the matrix.^[83] Glycosylation variants of fibronectin, including those with oncofetal glycosylations, affect its solubility and folding, with more processed glycans generally conferring greater solubility compared to high-mannose forms.^[14]^[84] Limited proteolysis by matrix metalloproteinase-9 (MMP-9) generates bioactive fragments from fibronectin, which can exhibit distinct functions such as promoting cell migration or inhibiting proliferation, separate from the intact protein.^[85] Regulatory enzymes further modulate fibronectin through cleavage and degradation pathways. ADAMTS proteases, such as ADAMTS3 and ADAMTS9, cleave fibronectin during extracellular matrix remodeling, contributing to tissue adaptation and turnover.^[86]^[87] Ubiquitination targets fibronectin for lysosomal degradation, a process that is constitutive but can be enhanced by stressors like UV irradiation; reduced ubiquitination leads to accumulation of specific isoforms, such as fibronectin-EDA, in fibrotic conditions.^[88]^[89] Recent studies have highlighted fibronectin's interactions with vascular endothelial growth factor (VEGF) in modulating angiogenesis. Fibronectin exposes cryptic VEGF-binding sites upon heparin-induced conformational changes, enhancing VEGF presentation to endothelial cells and promoting vascular sprouting; these pH-sensitive interactions are similarly utilized by VEGFR2.^[90]^[91] In pathological contexts, such as retinal angiogenesis, fibronectin facilitates endothelial-to-mesenchymal transition, amplifying VEGF-driven vessel instability as observed in 2025 investigations.^[92]

References

[1]
Fibronectin: Molecular Structure, Fibrillar Structure and ... - NIH
FN is assembled by cells into viscoelastic fibrils that can bind upward of 40 distinct growth factors and cytokines.
[2]
Plasma and cellular fibronectin: distinct and independent functions ...
Sep 16, 2011 · It functions both as a regulator of cellular processes and an important scaffolding protein to maintain and direct tissue organization and ECM ...Cellular Fibronectin · Fibronectin In The Late... · Fibronectin-Matrix Assembly
[3]
Fibronectins, Their Fibrillogenesis, and In Vivo Functions - PMC
Each FN monomer has a modular structure consisting of 12 type I repeats (cylinders), 2 type II repeats (diamonds), and 15 constitutive type III repeats ( ...
[4]
https://doi.org/10.1007/978-1-4612-3268-8
[5]
https://pubmed.ncbi.nlm.nih.gov/10940509/
[6]
The Evolution of Extracellular Matrix - PMC - NIH
ECM evolved with metazoa, showing conservation and innovation. Many components predate metazoa, with later innovations in deuterostomes and vertebrates.
[7]
New insights into form and function of Fibronectin Splice Variants
The fifteen Type III modules constitute the largest part of the FN polypeptide and are clustered in the central part of the protein (Figure 1A).
[8]
Regulation of Fibronectin EDA Exon Alternative Splicing
The fibronectin primary transcript undergoes alternative splicing in three noncoordinated sites: the cassette-type EDA and EDB exons and the more complex IIICS ...Missing: CS | Show results with:CS
[9]
Plasma and cellular fibronectin: distinct and independent functions ...
Sep 16, 2011 · In this paper, we discuss the differences in the structure of plasma and cellular FN, and their roles during the different stages of tissue repair.
[10]
Fibronectin: Molecular Structure, Fibrillar Structure and ... - MDPI
EDA and EDB domains are almost exclusively spliced out from pFN, 50% of which also lack IIICS, whereas cFN exhibits greater heterogeneity, containing none, one ...<|separator|>
[11]
Alternative splicing of fibronectin: Three variants, three functions
Recently, progress has been made in the identification of specific activities for the three Variants of the V region, V120, V95, and V0. FN-mediated cell ...
[12]
Fibronectin in development and wound healing - ScienceDirect.com
FN is normally expressed in tissue (EDA− and EDB−); however, wound base cells express the alternatively spliced EDA+ and EDB+, mimicking the splicing pattern ...
[13]
Fibronectin Extra Domains tune cellular responses and confer ...
Feb 24, 2021 · We demonstrate that the presence of one or both extra domains impacts FN assembly, function and physical properties of the matrix.
[14]
Regulated splicing of the fibronectin EDA exon is essential for ...
The alternative splicing process is cell type-, developmentally, and age regulated. The EDA and EDB are single exons coding for single type III repeats that are ...
[15]
Alternatively Spliced EDA Segment Regulates Fibronectin ...
These results indicated that alternative splicing in the EDA region regulates FN-mediated extracellular signals and subsequent cell cycle progression via.
[16]
Exploring the mechanism of fibronectin extra domain B in the tumor ...
FN-EDB also promotes tumor angiogenesis by upregulating factors like VEGF and matrix metalloproteinases, providing necessary nutrients and oxygen for tumor ...
[17]
Exploring the mechanism of fibronectin extra domain B in the tumor ...
Apr 10, 2025 · FN‐EDB plays a key role in tumor cell adhesion, angiogenesis and invasion, and is closely related to tumor malignancy and poor prognosis.
[18]
Exploring the mechanism of fibronectin extra domain B in the tumor ...
Apr 10, 2025 · FN-EDB plays a key role in tumor cell adhesion, angiogenesis and invasion, and is closely related to tumor malignancy and poor prognosis.
[19]
Cell attachment activity of fibronectin can be duplicated by ... - Nature
May 3, 1984 · Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Michael D. Pierschbacher &; Erkki ...Missing: paper | Show results with:paper
[20]
Defining Fibronectin's Cell Adhesion Synergy Site by Site-Directed ...
Fibronectin's RGD-mediated binding to the α5β1 integrin is dramatically enhanced by a synergy site within fibronectin III domain 9 (FN9).
[21]
Fibronectin promotes directional persistence in fibroblast migration ...
Jun 16, 2017 · We recently demonstrated that elevated surface density of physically adsorbed plasma fibronectin (FN) promotes high directional persistence in fibroblast ...
[22]
Targeting integrin pathways: mechanisms and advances in therapy
Jan 2, 2023 · The RGD peptide is the common binding motif of these RGD-binding integrins in the ECM (e.g., fibronectin, osteopontin, vitronectin, and ...Missing: seminal | Show results with:seminal<|control11|><|separator|>
[23]
Cellular mechanotransduction in health and diseases - Nature
Jul 31, 2023 · A stiffening keloid matrix activates integrins to induce gene expression through FAK/ERK signaling pathway and interacts with TGFβ/Smad cascades ...
[24]
Characterisation of fibronectin-mediated FAK signalling pathways in ...
Jun 30, 2009 · Our data suggest that fibronectin-mediated activation of FAK that leads to lung cancer metastasis could occur through ERK or PI3K/Akt regulation.
[25]
FibronectinEDA promotes chronic cutaneous fibrosis through Toll ...
Apr 16, 2014 · Exogenous Fn(EDA) was a potent stimulus for collagen production, myofibroblast differentiation, and wound healing in vitro and increased the ...
[26]
Integrin α4β1 and TLR4 Cooperate to Induce Fibrotic Gene ...
Our studies indicate that the fibronectin EDA domain drives two waves of gene expression in human dermal fibroblasts. The first wave, seen at 2 hours, consisted ...
[27]
TGF-β-induced epithelial to mesenchymal transition | Cell Research
Jan 20, 2009 · TGF-β signaling has been shown to play an important role in EMT. In fact, adding TGF-β to epithelial cells in culture is a convenient way to induce EMT in ...
[28]
β-catenin activates TGF-β-induced epithelial–mesenchymal ... - Nature
Oct 15, 2020 · Crosstalk between TGF-β/Smad signaling and Wnt/β-catenin signaling is important in developmental and pathological events. TGF-β signaling ...Results · Tgf-β2 Is A Direct Target... · β-Catenin Leads To...<|separator|>
[29]
Wnt signaling pathways in biology and disease - Nature
Apr 4, 2025 · Crosstalk between the Wnt and TGF-β pathways modulates cellular responses to external stimuli, fine-tuning growth, differentiation, and ...
[30]
Structure of integrin α 5 β 1 in complex with fibronectin - EMBO Press
The dissociation constant of Fn9–10 from this maximally activated α5β1 headpiece was calculated from the sensorgrams as 1.68 ± 0.57 nM (n = 5). This value ...Missing: Kd | Show results with:Kd<|separator|>
[31]
Mechanical regulation of a molecular clutch defines force ... - PubMed
Force transduction is triggered by talin unfolding above a stiffness threshold. Below this threshold, integrins unbind and release force before talin can unfold ...Missing: dependent | Show results with:dependent
[32]
The force loading rate drives cell mechanosensing through both ...
Jul 9, 2021 · We find that increasing loading rates trigger talin-dependent mechanosensing, leading to adhesion growth and reinforcement, and YAP nuclear localization.
[33]
FN1 gene: MedlinePlus Genetics
Apr 1, 2015 · Genomic Location. The FN1 gene is found on chromosome 2. Related Health Topics. Genes and Gene Therapy · Genetic Disorders. MEDICAL ENCYCLOPEDIA.
[34]
Regulation of fibronectin synthesis by interleukin-1 and interleukin-6 ...
The authors have observed previously that recombinant human interleukin-1 (rhIL-1) administered into rats increased plasma fibronectin (Fn) level ...Missing: transcription | Show results with:transcription
[35]
and O-Glycosylation Analysis of Human Plasma Fibronectin - NIH
Here, we performed a comprehensive N- and O-glycosylation mapping of human plasma fibronectin and quantified the occurrence of each glycoform in a site-specific ...
[36]
Selective secretion of alternatively spliced fibronectin variants - PMC
Alternative splicing of the V segment of the rat FN transcript generates three subunit variants (V120, V95, V0) that differ by the inclusion or omission of an ...
[37]
Role of hypoxia-induced fibronectin-integrin β1 expression in ...
Hypoxia increases the proliferation and migration of mESCs via FN-IN β1 production through the PI3K/Akt, mTOR, and HIF-1α pathways, followed by FAK activation.Missing: secretion FN1 gene regulation biosynthesis glycosylation dimerization mechanisms
[38]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2115891/
[39]
https://pubmed.ncbi.nlm.nih.gov/20677223/
[40]
The emergence of integrins: a personal and historical perspective.
The concept that there must exist transmembrane connections between extracellular matrix proteins and the actin-based cytoskeleton developed during the 1970s.
[41]
Integrin α5β1 and Fibronectin Regulate Polarized Cell Protrusions ...
May 9, 2006 · Integrin recognition of fibronectin is required for normal gastrulation including the mediolateral cell intercalation behaviors that drive ...Fibronectin Protein... · Fn/integrin Interactions... · Exogenous Integrin...
[42]
Mesodermal development in mouse embryos mutant for fibronectin
Three independent mutations were made by homologous recombination in two different regions of the fibronectin (FN) gene; all three appeared to be functional ...Missing: implantation | Show results with:implantation
[43]
Fibronectins in Vascular Morphogenesis - PMC - PubMed Central
Fibronectin (FN) is an extracellular matrix protein, essential for blood vessel morphogenesis; it is incorporated between endothelial and perivascular cells.
[44]
Basement membrane components are key players in specialized ...
BMs are specialized extracellular matrices (sECMs) with unique components that support important functions including differentiation, proliferation, migration, ...Missing: turnover | Show results with:turnover
[45]
The extracellular matrix niche of muscle stem cells - ScienceDirect
In this review, we explore the interplay between stem cells and their niches, with a primary focus on skeletal muscle stem cells and the extracellular matrix ( ...
[46]
Extracellular Matrix Degradation and Remodeling in Development ...
The serine protease plasmin degrades matrix proteins such as fibrin, fibronectin ... In many cases basement membrane breakdown is neither complete nor permanent.
[47]
Novel fibrin-fibronectin matrix accelerates mice skin wound healing
Plasma fibrinogen (F1) and fibronectin (pFN) polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound healing.
[48]
Role of fibronectin in normal wound healing - PMC - NIH
Jun 7, 2013 · Plasma fibronectin is more important in the early phase of wound healing where it binds to platelets and fibrin, resulting in providing ...Missing: hemostasis | Show results with:hemostasis
[49]
Fibronectin and wound healing - PubMed - NIH
In terms of tissue remodeling, fibronectin functions as a nonimmune opsonin for phagocytosis of debris by fibroblasts, keratinocytes, and under some ...
[50]
Fibronectin in tissue regeneration: timely disassembly of the scaffold ...
To benefit tissue regeneration, fibronectin promotes opsonization of tissue debris, migration, proliferation, and contraction of cells involved in the healing ...Missing: phase | Show results with:phase
[51]
Keratinocyte Interactions with Fibronectin during Wound Healing
Plasma contains 300 mg/ml of fibronectin, and it becomes incorporated into the blood clot with fibrin. The role of clot-bound plasma fibronectin has been ...
[52]
The fibronectin ED-A domain enhances recruitment of latent TGF-β ...
Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan. J. Cell Biol. 162, 149-160. 10.1083/jcb ...
[53]
Expression and Biological Activity Analysis of Recombinant ... - NIH
Jun 23, 2025 · When combined with biomaterials, nanofiber scaffolds loaded with FN can facilitate the migration and adhesion of dental mesenchymal cells, thus ...
[54]
Enhanced wound healing function of fibronectin variants via fusing ...
Small molecular recombinant fibronectins were engineered via fusing with PF4. Recombinant FNs can be expressed in E. coli and has good biological function.
[55]
Integrins in Wound Healing - PMC - PubMed Central - NIH
They create the granulation tissue along with the activated fibroblasts, mesenchymal progenitor cells (pericytes and other mesenchymal stem cells), and ...
[56]
Principles of Wound Healing - Mechanisms of Vascular Disease
Chronic leg ulcers were also found to contain elevated MMP-2 and MMP-9, and that fibronectin degradation in chronic wounds was dependent on the relative levels ...Haemostasis · Proliferative Phase · Collagen And Extracellular...
[57]
Matrix remodeling by MMPs during wound repair - ScienceDirect.com
MMPs can contribute to resolution of scarring and fibrosis by either directly by degrading ECM or indirectly by shaping the proteolytic phenotype of cells [4], ...
[58]
Fibronectin in hyperglycaemia and its potential use in the treatment ...
Dec 19, 2022 · Wound healing is impaired in diabetes. The inflammatory phase in a normal wound is transient and converted to the proliferative phase that ...
[59]
Topical Fibronectin Improves Wound Healing of Irradiated Skin - NIH
Jun 20, 2017 · Wound healing is significantly delayed in irradiated skin. To better understand global changes in protein expression after radiation, ...Missing: trials | Show results with:trials
[60]
Fibronectin matrix mimetic, Chimectin as a first-in ... - NIH RePORTER
Fibronectin matrix mimetics promote cell adhesion, proliferation, migration and contractility, modulate extracellular matrix composition, and induce local ...
[61]
Topical application of plasma fibronectin in full-thickness skin wound ...
The purpose of this study was to investigate whether topical application of plasma Fn (pFn) improves healing of full-thickness skin wounds in rats. A round ...Missing: clinical trials
[62]
2335 - Gene ResultFN1 fibronectin 1 [ (human)] - NCBI
Sep 27, 2025 · This gene encodes fibronectin, a glycoprotein present in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and in ...
[63]
Rare genetic variation in fibronectin 1 (FN1) protects against ...
Apr 10, 2024 · Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk.
[64]
https://reporter.nih.gov/search/FKYEH9S8IUyyf4fkTRSwdA/project-details/10917587
[65]
Thrombomodulin promotes focal adhesion kinase activation and ...
Fibronectin was reported to bind to a number of important molecules, including heparin, fibrin, collagen, gelatin, and integrins [1]. ... protein-protein ...
[66]
Recombinant DTβ4-inspired porous 3D vascular graft enhanced ...
Jul 13, 2022 · ... fibrin, thereafter offers opening ... CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.
[67]
Phosphorylated fibronectin enhances cell attachment and ...
Jul 10, 2019 · Controlled in vitro phosphorylation of fibronectin by a casein kinase II (CKII) significantly upregulated cell traction forces and total strain ...Missing: Ser2116 | Show results with:Ser2116
[68]
Uncovering protein glycosylation dynamics and heterogeneity using ...
Feb 10, 2025 · Application of glyco solubility proteome profiling showed that high-mannose glycoforms tend to be more soluble than more processed glycans (Fig.
[69]
Matrix Metalloproteinase-9: Many Shades of Function in ...
Nov 1, 2013 · Several ECM proteins are proteolytically processed by MMP-9, including collagen, fibronectin, and laminin. ECM fragments are known to express ...
[70]
Their Multifaceted Role in the Regulation of Cancer Metastasis - PMC
ADAMTS3 secreted by myoepithelial cells inhibits BC cell invasion through cleavage of fibronectin (FN). D. ADAMTS1 was found to cleave syndecan-4 (SDCN4) in ...
[71]
A disintegrin-like and metalloproteinase domain with ...
These findings, along with stronger fibronectin staining previously observed in Adamts9 mutant embryos, suggest that ADAMTS9 contributes to fibronectin turnover ...
[72]
Constitutive and UV-induced Fibronectin Degradation Is a ...
Fibronectin Undergoes Ubiquitination and Degradation upon UV Irradiation—Treatment of cells with genotoxic agents such as UV irradiation, X-rays, and ...
[73]
Fibronectin-EDA accumulates via reduced ubiquitination ...
Fibronectin-EDA accumulates via reduced ubiquitination downstream of Toll-like receptor 9 activation in SSc-ILD fibroblasts.
[74]
The role of extracellular matrix in angiogenesis: Beyond adhesion ...
These tip cells secret an array of matrix degrading enzymes, particularly matrix metalloproteases (MMPs) including 1, 2, 9 and MTI-MMP, to breakdown basement ...
[75]
VEGF and VEGFR2 bind to similar pH-sensitive sites on fibronectin ...
The VEGFR2-binding sites on fibronectin show great similarity to the VEGF-binding sites, as they were also exposed upon heparin-induced conformational changes.
[76]
Fibronectin Mediates Endothelial-to-Mesenchymal Transition in ...
Mar 5, 2025 · The purpose of this study was to investigate the role of endothelial-mesenchymal transition (EndoMT) in pathological retinal angiogenesis ...