- Fibronectin is a high-molecular-weight glycoprotein of the extracellular matrix (ECM) that plays a crucial role in cell adhesion, migration, growth, and differentiation.
- It is a key component of the ECM and interacts with cell surface receptors, particularly integrins, to mediate communication between cells and their surrounding environment. Fibronectin is found in virtually all vertebrate tissues and exists in two major forms: soluble plasma fibronectin, which circulates in the blood, and insoluble cellular fibronectin, which is assembled into fibrillar networks in the ECM.
- Structurally, fibronectin is a dimeric molecule, composed of two nearly identical monomers (~220–250 kDa each) that are covalently linked near their C-termini by a pair of disulfide bonds. Each monomer consists of a series of repeating modules classified into type I, type II, and type III repeats. These domains provide binding sites for various ECM components (e.g., collagen, heparin) and cell surface receptors (e.g., integrins). A hallmark of fibronectin is the presence of the RGD (Arg-Gly-Asp) motif located within the type III10 repeat, which is recognized by integrins such as α5β1 and αvβ3, facilitating cell adhesion.
- Fibronectin’s ability to bind multiple ligands makes it a multi-domain scaffold protein, coordinating the spatial and mechanical properties of the ECM. It can bind not only to integrins, but also to other ECM proteins like collagen, fibrin, and heparan sulfate proteoglycans, enabling crosslinking and structural integrity of the matrix. The fibrillar form of fibronectin is dynamically assembled on the cell surface through a process called fibronectin fibrillogenesis, which requires integrin-mediated tension and actin cytoskeleton contractility. This fibrillogenesis is essential for ECM remodeling and tissue repair.
- Fibronectin is also heavily involved in developmental processes, including embryogenesis, organ morphogenesis, and neural crest migration. In adults, it contributes to wound healing, angiogenesis, and immune cell trafficking. During wound repair, plasma fibronectin is deposited at the injury site and acts as a provisional matrix that supports platelet aggregation and fibroblast adhesion. Later, fibroblasts replace this with a fibronectin-rich matrix that facilitates tissue regeneration.
- The expression and alternative splicing of fibronectin are tightly regulated. The FN1 gene, located on human chromosome 2q35, undergoes complex alternative splicing, resulting in multiple isoforms. Two important splice variants are the inclusion of the EDA (Extra Domain A) and EDB (Extra Domain B) segments, which are generally absent in plasma fibronectin but present in cellular fibronectin during embryogenesis, tissue remodeling, or pathological conditions like cancer and fibrosis.
- Fibronectin also plays a significant role in disease. Aberrant fibronectin expression or organization is implicated in cancer, fibrosis, and cardiovascular diseases. In cancer, fibronectin promotes tumor progression, angiogenesis, and metastasis by enhancing integrin signaling and ECM remodeling. Tumor cells often exploit fibronectin-enriched microenvironments to migrate and invade surrounding tissues. In fibrotic disorders, excessive deposition of fibronectin contributes to scar tissue formation and organ dysfunction. Moreover, circulating fibronectin levels are elevated in various inflammatory and cardiovascular diseases, reflecting ongoing tissue remodeling and inflammation.
- Fibronectin functions not only as a structural ECM protein but also as a mechanotransducer, conveying mechanical signals from the ECM to the intracellular environment through integrins. This integrin-fibronectin interaction can activate intracellular pathways such as FAK/Src, PI3K/Akt, and MAPK, influencing gene expression and cell behavior.
- In summary, fibronectin is a multifunctional ECM glycoprotein critical for maintaining tissue architecture, mediating cell–ECM interactions, and regulating cellular responses during development, repair, and disease. Its complex domain structure, versatile binding capabilities, and dynamic regulation make it an essential player in both normal physiology and pathological conditions. Ongoing research continues to uncover novel roles for fibronectin in mechanobiology and as a therapeutic target in diseases characterized by abnormal ECM remodeling.
