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Fibronectin 1

PDB rendering based on 1e88.
Available structures
1e88, 1e8b, 1fbr, 1fna, 1fnf, 1fnh, 1j8k, 1o9a, 1oww, 1q38, 1qgb, 1qo6, 1ttf, 1ttg, 2cg6, 2cg7, 2cku, 2fn2, 2fnb, 2gee, 2h41, 2h45, 2ha1
Symbols FN1; CIG; DKFZp686F10164; DKFZp686H0342; DKFZp686I1370; DKFZp686O13149; FINC; FN; LETS; MSF
External IDs OMIM135600 MGI95566 HomoloGene1533 GeneCards: FN1 Gene
RNA expression pattern
PBB GE FN1 210495 x at tn.png
PBB GE FN1 211719 x at tn.png
PBB GE FN1 212464 s at tn.png
More reference expression data
Species Human Mouse
Entrez 2335 14268
Ensembl ENSG00000115414 ENSMUSG00000026193
UniProt P02751 Q3UZF9
RefSeq (mRNA) NM_002026 NM_010233
RefSeq (protein) NP_002017 NP_034363
Location (UCSC) Chr 2:
215.93 - 216.01 Mb
Chr 1:
71.52 - 71.59 Mb
PubMed search [1] [2]

Fibronectin is a high-molecular weight (~440kDa) extracellular matrix glycoprotein that binds to membrane-spanning receptor proteins called integrins.[1] In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans (e.g. syndecans).

Fibronectin exists as a dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds.[1] The fibronectin protein is produced from a single gene, but alternative splicing of its pre-mRNA leads to the creation of several isoforms.

Two types of fibronectin are present in vertebrates:[1]

Fibronectin plays a major role in cell adhesion, growth, migration and differentiation, and it is important for processes such as wound healing and embryonic development.[1] Altered fibronectin expression, degradation, and organization has been associated with a number of pathologies, including cancer and fibrosis.[2]



Fibronectin exists as a dimer, consisting of two nearly identical polypeptide chains linked by a pair of C-terminal disulfide bonds.[3] Each fibronectin monomer has a molecular weight of 230-250 kDa and contains three types of modules: type I, II, and III. All three modules are composed of two anti-parallel β-sheets; however, type I and type II are stabilized by intra-chain disulfide bonds, while type III modules do not contain any disulfide bridges. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.[4]

Three regions of variable splicing occur along the length of the fibronectin monomer.[3] One or both of the "extra" type III modules (EIIIA and EIIIB) may be present in cellular fibronectin, but they are never present in plasma fibronectin. A "variable" V-region exists between III14-15 (the 14th and 15th type III module). The V-region structure is different from the type I, II, and III modules, and its presence and length may vary. The V-region contains the binding site for α4β1 integrins. It is present in most cellular fibronectin, but only one of the two subunits in a plasma fibronectin dimer contains a V-region sequence.

The modules are arranged into several functional and protein-binding domains along the length of a fibronectin monomer. There are four fibronectin-binding domains, allowing fibronectin to associate with other fibronectin molecules.[3] One of these fibronectin-binding domains, I1-5, is referred to as the "assembly domain", and it is required for the initiation of fibronectin matrix assembly. Modules III9-10 correspond to the "cell-binding domain" of fibronectin. The RGD sequence (Arg–Gly–Asp) is located in III10 and is the site of cell attachment via α5β1 and αVβ3 integrins on the cell surface. The "synergy site" is in III9 and has a role in modulating fibronectin's accociation with α5β1 integrins.[5] Fibronectin also contains domains for fibrin-binding (I1-5, I10-12), collagen-binding (I6-9), fibulin-1-binding (III13-14), heparin-binding and syndecan-binding (III12-14).[3]

The Modular Structure of Fibronectin with its Binding Domains


Fibronectin has numerous functions that ensure the normal functioning of vertebrate organisms.[1] It is involved in cell adhesion, growth, migration and differentiation. Cellular fibronectin is assembled into the extracellular matrix, an insoluble network that separates and supports the organs and tissues of an organism.

Fibronectin plays a crucial role in wound healing.[6] Along with fibrin, plasma fibronectin is deposited at the site of injury, forming a blood clot that stops bleeding and protects the underlying tissue. As repair of the injured tissue continues, fibroblasts and macrophages begin to remodel the area, degrading the proteins that form the provisional blood clot matrix and replacing them with a matrix that more resembles the normal, surrounding tissue. Fibroblasts secrete proteases, including matrix metalloproteinases, that digest the plasma fibronectin, and then the fibroblasts secrete cellular fibronectin and assemble it into an insoluble matrix. Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step in wound healing. Fragmenting fibronectin further exposes its V-region, which contains the site for α4β1 integrin-binding. These fragments of fibronectin are believed to enhance α4β1 integrins-expressing cell binding, allowing them to adhere to and forcefully contract the surrounding matrix.

Fibronectin is necessary for embryogenesis, and inactivating the gene for fibronectin results in early embryonic lethality.[7] Fibronectin is important for guiding cell attachment and migration during embryonic development. In mammalian development, the absence of fibronectin leads to defects in mesodermal, neural tube, and vascular development. Similarly, the absence of a normal fibronectin matrix in developing amphibians causes defects in mesodermal patterning and inhibits gastrulation.[8]

Fibronectin is also found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by potentially pathogenic bacteria.[9]

Matrix assembly

Cellular fibronectin is assembled into an insoluble fibrillar matrix in a complex cell-mediated process.[10] Fibronectin matrix assembly begins when soluble, compact fibronectin dimers are secreted from cells, often fibroblasts. These soluble dimers bind to α5β1 integrin receptors on the cell surface and aide in clustering the integrins. The local concentration of integrin-bound fibronectin increases, allowing bound fibronectin molecules to more readily interact with one another. Short fibronectin fibrils then begin to form between adjacent cells. As matrix assembly proceeds, the soluble fibrils are converted into larger insoluble fibrils that comprise the extracellular matrix.

Fibronectin’s shift from soluble to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecules. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. This force partially unfolds the fibronectin ligand, unmasking cryptic fibronectin-binding sites and allowing nearby fibronectin molecules to associate. This fibronectin-fibronectin interaction enables the soluble, cell-associated fibrils to branch and stabilize into an insoluble fibronectin matrix.

Role in cancer

Several of the morphological changes observed in tumors and tumor-derived cell lines have been attributed to decreased fibronectin expression, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, such as α5β1 integrins.[11]

Fibronectin has been implicated in carcinoma development.[12] In lung carcinoma, fibronectin expression is increased, especially in non-small cell lung carcinoma. The adhesion of lung carcinoma cells to fibronectin enhances tumorigenicity and confers resistance to apoptosis-inducing chemotherapeutic agents. Fibronectin has been shown to stimulate the gonadal steroids that interact with vertebrate androgen receptors, which are capable of controlling the expression of cyclin D and related genes involved in cell cycle control. These observations suggest that fibronectin may promote lung tumor growth/survival and resistance to therapy, and it could represent a novel target for the development of new anticancer drugs.


Fibronectin has been shown to interact with Collagen, type VII, alpha 1,[13][14] TRIB3,[15] Lipoprotein(a),[16] Tenascin C,[17] CD44[18] and IGFBP3.[19][20]


  1. ^ a b c d e Pankov R, Yamada KM (October 2002). "Fibronectin at a glance". Journal of cell science 115 (Pt 20): 3861–3. doi:10.1242/jcs.00059. PMID 12244123.  
  2. ^ Williams CM, Engler AJ, Slone RD, Galante LL, Schwarzbauer JE (May 2008). "Fibronectin expression modulates mammary epithelial cell proliferation during acinar differentiation". Cancer research 68 (9): 3185–92. doi:10.1158/0008-5472.CAN-07-2673. PMID 18451144.  
  3. ^ a b c d Mao Y, Schwarzbauer JE (September 2005). "Fibronectin fibrillogenesis, a cell-mediated matrix assembly process". Matrix biology : journal of the International Society for Matrix Biology 24 (6): 389–99. doi:10.1016/j.matbio.2005.06.008. PMID 16061370.  
  4. ^ Erickson HP (2002). "Stretching fibronectin". Journal of muscle research and cell motility 23 (5-6): 575–80. doi:10.1023/A:1023427026818. PMID 12785106.  
  5. ^ Sechler JL, Corbett SA, Schwarzbauer JE (December 1997). "Modulatory roles for integrin activation and the synergy site of fibronectin during matrix assembly". Molecular biology of the cell 8 (12): 2563–73. PMID 9398676. PMC 25728.  
  6. ^ Valenick LV, Hsia HC, Schwarzbauer JE (September 2005). "Fibronectin fragmentation promotes alpha4beta1 integrin-mediated contraction of a fibrin-fibronectin provisional matrix". Experimental cell research 309 (1): 48–55. doi:10.1016/j.yexcr.2005.05.024. PMID 15992798.  
  7. ^ George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO (December 1993). "Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin". Development (Cambridge, England) 119 (4): 1079–91. PMID 8306876.  
  8. ^ Darribère T, Schwarzbauer JE (April 2000). "Fibronectin matrix composition and organization can regulate cell migration during amphibian development". Mechanisms of development 92 (2): 239–50. doi:10.1016/S0925-4773(00)00245-8. PMID 10727862.  
  9. ^ Hasty DL, Simpson WA (September 1987). "Effects of fibronectin and other salivary macromolecules on the adherence of Escherichia coli to buccal epithelial cells". Infection and immunity 55 (9): 2103–9. PMID 3305363. PMC 260663.  
  10. ^ Wierzbicka-Patynowski I, Schwarzbauer JE (August 2003). "The ins and outs of fibronectin matrix assembly". Journal of cell science 116 (Pt 16): 3269–76. doi:10.1242/jcs.00670. PMID 12857786.  
  11. ^ Hynes, Richard O. (1990). Fibronectins. Berlin: Springer-Verlag. ISBN 0-387-97050-9.  
  12. ^ Han S, Khuri FR, Roman J (January 2006). "Fibronectin stimulates non-small cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways". Cancer research 66 (1): 315–23. doi:10.1158/0008-5472.CAN-05-2367. PMID 16397245.  
  13. ^ Lapiere, J C; Chen J D, Iwasaki T, Hu L, Uitto J, Woodley D T (Nov. 1994). "Type VII collagen specifically binds fibronectin via a unique subdomain within the collagenous triple helix". J. Invest. Dermatol. (UNITED STATES) 103 (5): 637–41. doi:10.1111/1523-1747.ep12398270. ISSN 0022-202X. PMID 7963647.  
  14. ^ Chen, M; Marinkovich M P, Veis A, Cai X, Rao C N, O'Toole E A, Woodley D T (Jun. 1997). "Interactions of the amino-terminal noncollagenous (NC1) domain of type VII collagen with extracellular matrix components. A potential role in epidermal-dermal adherence in human skin". J. Biol. Chem. (UNITED STATES) 272 (23): 14516–22. doi:10.1074/jbc.272.23.14516. ISSN 0021-9258. PMID 9169408.  
  15. ^ Zhou, Ying; Li Lu, Liu Qiongming, Xing Guichun, Kuai Xuezhang, Sun Jing, Yin Xiushan, Wang Jian, Zhang Lingqiang, He Fuchu (May. 2008). "E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3". Cell. Signal. (England) 20 (5): 942–8. doi:10.1016/j.cellsig.2008.01.010. ISSN 0898-6568. PMID 18276110.  
  16. ^ Salonen, E M; Jauhiainen M, Zardi L, Vaheri A, Ehnholm C (Dec. 1989). "Lipoprotein(a) binds to fibronectin and has serine proteinase activity capable of cleaving it". EMBO J. (ENGLAND) 8 (13): 4035–40. ISSN 0261-4189. PMID 2531657.  
  17. ^ Chung, C Y; Zardi L, Erickson H P (Dec. 1995). "Binding of tenascin-C to soluble fibronectin and matrix fibrils". J. Biol. Chem. (UNITED STATES) 270 (48): 29012–7. doi:10.1074/jbc.270.48.29012. ISSN 0021-9258. PMID 7499434.  
  18. ^ Jalkanen, S; Jalkanen M (Feb. 1992). "Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin". J. Cell Biol. (UNITED STATES) 116 (3): 817–25. doi:10.1083/jcb.116.3.817. ISSN 0021-9525. PMID 1730778.  
  19. ^ Martin, J A; Miller B A, Scherb M B, Lembke L A, Buckwalter J A (Jul. 2002). "Co-localization of insulin-like growth factor binding protein 3 and fibronectin in human articular cartilage". Osteoarthr. Cartil. (England) 10 (7): 556–63. doi:10.1053/joca.2002.0791. ISSN 1063-4584. PMID 12127836.  
  20. ^ Gui, Y; Murphy L J (May. 2001). "Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) binds to fibronectin (FN): demonstration of IGF-I/IGFBP-3/fn ternary complexes in human plasma". J. Clin. Endocrinol. Metab. (United States) 86 (5): 2104–10. doi:10.1210/jc.86.5.2104. ISSN 0021-972X. PMID 11344214.  

Further reading

See also

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