Fibronectin: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
[[File:The Modular Structure of Fibronectin and its Binding Domains.png|thumb|right|400px|The modular structure of fibronectin and its binding domains]]
[[File:The Modular Structure of Fibronectin and its Binding Domains.png|thumb|right|400px|The modular structure of fibronectin and its binding domains]]
'''Fibronectin''' is a high-[[molecular weight]] (~440kDa) [[glycoprotein]] of the [[extracellular matrix]] that binds to [[cell membrane|membrane]]-spanning [[receptor proteins]] called [[integrins]].<ref name="pmid12244123">{{cite journal | vauthors = Pankov R, Yamada KM | title = Fibronectin at a glance | journal = Journal of Cell Science | volume = 115 | issue = Pt 20 | pages = 3861–3 | date = Oct 2002 | pmid = 12244123 | doi = 10.1242/jcs.00059 }}</ref> Similar to integrins, fibronectin binds extracellular matrix components such as [[collagen]], [[fibrin]], and [[heparan sulfate]] [[proteoglycans]] (e.g. [[syndecans]]).
'''Fibronectin''' is a high-[[molecular weight]] (~440kDa) [[glycoprotein]] of the [[extracellular matrix]] that binds to [[cell membrane|membrane]]-spanning [[receptor proteins]] called [[integrins]].<ref name="pmid12244123">{{cite journal | vauthors = Pankov R, Yamada KM | title = Fibronectin at a glance | journal = Journal of Cell Science | volume = 115 | issue = Pt 20 | pages = 3861–3 | date = Oct 2002 | pmid = 12244123 | doi = 10.1242/jcs.00059 }}</ref> Fibronectin also binds to other extracellular matrix proteins such as [[collagen]], [[fibrin]], and [[heparan sulfate]] [[proteoglycans]] (e.g. [[syndecans]]).


Fibronectin exists as a [[protein dimer]], consisting of two nearly identical [[monomers]] linked by a pair of [[disulfide bonds]].<ref name="pmid12244123"/> The fibronectin protein is produced from a single gene, but [[alternative splicing]] of its [[pre-mRNA]] leads to the creation of several [[isoforms]].
Fibronectin exists as a [[protein dimer]], consisting of two nearly identical [[monomers]] linked by a pair of [[disulfide bonds]].<ref name="pmid12244123"/> The fibronectin protein is produced from a single gene, but [[alternative splicing]] of its [[pre-mRNA]] leads to the creation of several [[isoforms]].
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== Structure ==
== Structure ==
Fibronectin exists as a protein dimer, consisting of two nearly identical [[polypeptide]] chains linked by a pair of [[C-terminal]] [[disulfide bonds]].<ref name="pmid16061370">{{cite journal | vauthors = Mao Y, Schwarzbauer JE | title = Fibronectin fibrillogenesis, a cell-mediated matrix assembly process | journal = Matrix Biology | volume = 24 | issue = 6 | pages = 389–99 | date = Sep 2005 | pmid = 16061370 | doi = 10.1016/j.matbio.2005.06.008 }}</ref>  Each fibronectin [[Protein subunit|subunit]] has a molecular weight of 230–250 [[kDa]] and contains three types of [[protein module|modules]]: type I, II, and III.  All three modules are composed of two anti-parallel [[β-sheets]] resulting in a [[Beta-sandwich]]; however, [[Fibronectin type I domain|type I]] and [[Fibronectin type II domain|type II]] are stabilized by intra-chain disulfide bonds, while [[Fibronectin type III domain|type III]] modules do not contain any disulfide bonds. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.<ref name="pmid12785106">{{cite journal | vauthors = Erickson HP | title = Stretching fibronectin | journal = Journal of Muscle Research and Cell Motility | volume = 23 | issue = 5-6 | pages = 575–80 | year = 2002 | pmid = 12785106 | doi = 10.1023/A:1023427026818 }}</ref>
Fibronectin exists as a protein dimer, consisting of two nearly identical [[polypeptide]] chains linked by a pair of [[C-terminal]] [[disulfide bonds]].<ref name="pmid16061370">{{cite journal | vauthors = Mao Y, Schwarzbauer JE | title = Fibronectin fibrillogenesis, a cell-mediated matrix assembly process | journal = Matrix Biology | volume = 24 | issue = 6 | pages = 389–99 | date = Sep 2005 | pmid = 16061370 | doi = 10.1016/j.matbio.2005.06.008 }}</ref>  Each fibronectin [[Protein subunit|subunit]] has a molecular weight of 230–250 [[kDa]] and contains three types of [[protein module|modules]]: type I, II, and III.  All three modules are composed of two anti-parallel [[β-sheets]] resulting in a [[Beta-sandwich]]; however, [[Fibronectin type I domain|type I]] and [[Fibronectin type II domain|type II]] are stabilized by intra-chain disulfide bonds, while [[Fibronectin type III domain|type III]] modules do not contain any disulfide bonds. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.<ref name="pmid12785106">{{cite journal | vauthors = Erickson HP | title = Stretching fibronectin | journal = Journal of Muscle Research and Cell Motility | volume = 23 | issue = 5–6 | pages = 575–80 | year = 2002 | pmid = 12785106 | doi = 10.1023/A:1023427026818 }}</ref>


Three regions of variable [[RNA splicing|splicing]] occur along the length of the fibronectin [[protomer]].  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 III<sub>14–15</sub> (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.
Three regions of variable [[RNA splicing|splicing]] occur along the length of the fibronectin [[protomer]].  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 III<sub>14–15</sub> (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.
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Fibronectin’s shift from [[soluble]] to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecule. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. This [[force]] partially unfolds the fibronectin [[ligand (biochemistry)|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 [[extracellular matrix|matrix]].
Fibronectin’s shift from [[soluble]] to insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecule. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. This [[force]] partially unfolds the fibronectin [[ligand (biochemistry)|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 [[extracellular matrix|matrix]].
A transmembrane protein, CD93, has been shown to be essential for fibronectin matrix assembly (fibrillogenesis) in human dermal blood endothelial cells.<ref name="Lugano_2018">{{cite journal | vauthors = Lugano R, Vemuri K, Yu D, Bergqvist M, Smits A, Essand M, Johansson S, Dejana E, Dimberg A | title = CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis | journal = The Journal of Clinical Investigation | volume = 128 | issue = 8 | pages = 3280–3297 | date = August 2018 | pmid = 29763414 | pmc = 6063507 | doi = 10.1172/JCI97459 }}</ref> As a consequence, knockdown of CD93 in these cells resulted in the disruption of the fibronectin fibrillogenesis. Moreover, the CD93 knockout mice retinas displayed disrupted fibronectin matrix at the retinal sprouting front.<ref name="Lugano_2018" />


==Role in cancer==
==Role in cancer==
Several of the [[morphology (biology)|morphological]] changes observed in [[tumors]] and tumor-derived [[cell lines]] have been attributed to decreased fibronectin [[gene expression|expression]], increased fibronectin [[protein degradation|degradation]], and/or decreased [[gene expression|expression]] of fibronectin-binding [[receptor (biochemistry)|receptors]], such as [[α5β1]] [[integrins]].<ref name="isbn0-387-97050-9">{{cite book | author = Hynes, Richard O. | authorlink = | editor = | others = | title = Fibronectins | edition = | publisher = Springer-Verlag | location = Berlin | year = 1990 | origyear = | pages = | quote = | isbn = 0-387-97050-9 | oclc = | doi = | url = | accessdate = }}</ref>
Several morphological changes has been observed in [[tumors]] and tumor-derived [[cell lines]] that have been attributed to decreased fibronectin [[gene expression|expression]], increased fibronectin [[protein degradation|degradation]], and/or decreased [[gene expression|expression]] of fibronectin-binding [[receptor (biochemistry)|receptors]], such as [[α5β1]] [[integrins]].<ref name="isbn0-387-97050-9">{{cite book | author = Hynes, Richard O. | authorlink = | editor = | others = | title = Fibronectins | edition = | publisher = Springer-Verlag | location = Berlin | year = 1990 | origyear = | pages = | quote = | isbn = 0-387-97050-9 | oclc = | doi = | url = | accessdate = }}</ref>


Fibronectin has been implicated in [[carcinoma]] development.<ref name="pmid16397245">{{cite journal | vauthors = Han S, Khuri FR, Roman J | title = 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 | journal = Cancer Research | volume = 66 | issue = 1 | pages = 315–23 | date = Jan 2006 | pmid = 16397245 | doi = 10.1158/0008-5472.CAN-05-2367 }}</ref> In [[lung carcinoma]], fibronectin [[gene expression|expression]] is increased, especially in [[non-small cell lung carcinoma]]. The [[cell adhesion|adhesion]] of lung carcinoma cells to fibronectin enhances [[carcinogen|tumorigenicity]] and confers [[drug resistance|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 [[gene expression|expression]] of [[cyclin D]] and related [[genes]] involved in [[cell cycle]] control. These observations suggest that fibronectin may promote lung [[neoplasm|tumor growth]]/survival and resistance to therapy, and it could represent a novel [[biological target|target]] for the development of new [[anticancer drugs]].
Fibronectin has been implicated in [[carcinoma]] development.<ref name="pmid16397245">{{cite journal | vauthors = Han S, Khuri FR, Roman J | title = 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 | journal = Cancer Research | volume = 66 | issue = 1 | pages = 315–23 | date = Jan 2006 | pmid = 16397245 | doi = 10.1158/0008-5472.CAN-05-2367 }}</ref> In [[lung carcinoma]], fibronectin [[gene expression|expression]] is increased especially in [[non-small cell lung carcinoma]]. The [[cell adhesion|adhesion]] of lung carcinoma cells to fibronectin enhances [[carcinogen|tumorigenicity]] and confers [[drug resistance|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 [[gene expression|expression]] of [[cyclin D]] and related [[genes]] involved in [[cell cycle]] control. These observations suggest that fibronectin may promote lung [[neoplasm|tumor growth]]/survival and resistance to therapy, and it could represent a novel [[biological target|target]] for the development of new [[anticancer drugs]].


Fibronectin 1 acts as a potential [[biomarker]] for [[radioresistance]].<ref name="pmid20930522">{{cite journal | vauthors = Jerhammar F, Ceder R, Garvin S, Grénman R, Grafström RC, Roberg K | title = Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma | journal = Cancer Biology & Therapy | volume = 10 | issue = 12 | pages = 1244–1251 | date = Dec 2010 | pmid = 20930522 | doi = 10.4161/cbt.10.12.13432 }}</ref>
Fibronectin 1 acts as a potential [[biomarker]] for [[radioresistance]].<ref name="pmid20930522">{{cite journal | vauthors = Jerhammar F, Ceder R, Garvin S, Grénman R, Grafström RC, Roberg K | title = Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma | journal = Cancer Biology & Therapy | volume = 10 | issue = 12 | pages = 1244–1251 | date = Dec 2010 | pmid = 20930522 | doi = 10.4161/cbt.10.12.13432 }}</ref>


FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.<ref>{{cite journal | vauthors = Wasserman JK, Purgina B, Lai CK, Gravel D, Mahaffey A, Bell D, Chiosea SI | title = Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis | journal = Head and Neck Pathology | date = Jan 2016 | pmid = 26759148 | doi = 10.1007/s12105-015-0678-1 }}</ref><ref>{{cite journal | vauthors = Lee JC, Jeng YM, Su SY, Wu CT, Tsai KS, Lee CH, Lin CY, Carter JM, Huang JW, Chen SH, Shih SR, Mariño-Enríquez A, Chen CC, Folpe AL, Chang YL, Liang CW | title = Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour | journal = The Journal of Pathology | volume = 235 | issue = 4 | pages = 539–45 | date = Mar 2015 | pmid = 25319834 | doi = 10.1002/path.4465 }}</ref>
FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.<ref>{{cite journal | vauthors = Wasserman JK, Purgina B, Lai CK, Gravel D, Mahaffey A, Bell D, Chiosea SI | title = Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis | journal = Head and Neck Pathology | date = Jan 2016 | pmid = 26759148 | doi = 10.1007/s12105-015-0678-1 | volume=10 | pmc=4972751 | pages=279–85}}</ref><ref>{{cite journal | vauthors = Lee JC, Jeng YM, Su SY, Wu CT, Tsai KS, Lee CH, Lin CY, Carter JM, Huang JW, Chen SH, Shih SR, Mariño-Enríquez A, Chen CC, Folpe AL, Chang YL, Liang CW | title = Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour | journal = The Journal of Pathology | volume = 235 | issue = 4 | pages = 539–45 | date = Mar 2015 | pmid = 25319834 | doi = 10.1002/path.4465 }}</ref>


== Role in wound healing ==
== Role in wound healing ==
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* {{cite journal | vauthors = Przybysz M, Katnik-Prastowska I | title = [Multifunction of fibronectin] | language = Polish | journal = Postȩpy Higieny I Medycyny Doświadczalnej | volume = 55 | issue = 5 | pages = 699–713 | year = 2002 | pmid = 11795204 | doi =  |trans-title=Multifunction of fibronectin }}
* {{cite journal | vauthors = Przybysz M, Katnik-Prastowska I | title = [Multifunction of fibronectin] | language = Polish | journal = Postȩpy Higieny I Medycyny Doświadczalnej | volume = 55 | issue = 5 | pages = 699–713 | year = 2002 | pmid = 11795204 | doi =  |trans-title=Multifunction of fibronectin }}
* {{cite journal | vauthors = Rameshwar P, Oh HS, Yook C, Gascon P, Chang VT | title = Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis | journal = Acta Haematologica | volume = 109 | issue = 1 | pages = 1–10 | year = 2003 | pmid = 12486316 | doi = 10.1159/000067268 }}
* {{cite journal | vauthors = Rameshwar P, Oh HS, Yook C, Gascon P, Chang VT | title = Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis | journal = Acta Haematologica | volume = 109 | issue = 1 | pages = 1–10 | year = 2003 | pmid = 12486316 | doi = 10.1159/000067268 }}
* {{cite journal | vauthors = Cho J, Mosher DF | title = Role of fibronectin assembly in platelet thrombus formation | journal = Journal of Thrombosis and Haemostasis : JTH | volume = 4 | issue = 7 | pages = 1461–9  | date = Jul 2006 | pmid = 16839338 | doi = 10.1111/j.1538-7836.2006.01943.x }}
* {{cite journal | vauthors = Cho J, Mosher DF | title = Role of fibronectin assembly in platelet thrombus formation | journal = Journal of Thrombosis and Haemostasis | volume = 4 | issue = 7 | pages = 1461–9  | date = Jul 2006 | pmid = 16839338 | doi = 10.1111/j.1538-7836.2006.01943.x }}
* {{cite journal | vauthors = Schmidt DR, Kao WJ | title = The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function | journal = Biomaterials | volume = 28 | issue = 3 | pages = 371–82  | date = Jan 2007 | pmid = 16978691 | doi = 10.1016/j.biomaterials.2006.08.041 }}
* {{cite journal | vauthors = Schmidt DR, Kao WJ | title = The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function | journal = Biomaterials | volume = 28 | issue = 3 | pages = 371–82  | date = Jan 2007 | pmid = 16978691 | doi = 10.1016/j.biomaterials.2006.08.041 }}
* {{cite journal | vauthors = Dallas SL, Chen Q, Sivakumar P | title = Dynamics of assembly and reorganization of extracellular matrix proteins | journal = Current Topics in Developmental Biology | volume = 75 | issue =  | pages = 1–24 | year = 2006 | pmid = 16984808 | doi = 10.1016/S0070-2153(06)75001-3 }}
* {{cite journal | vauthors = Dallas SL, Chen Q, Sivakumar P | title = Dynamics of assembly and reorganization of extracellular matrix proteins | journal = Current Topics in Developmental Biology | volume = 75 | issue =  | pages = 1–24 | year = 2006 | pmid = 16984808 | doi = 10.1016/S0070-2153(06)75001-3 }}
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{{Globulins}}
{{Globulins}}


[[Category:Integrins]]
[[Category:Glycoproteins]]
[[Category:Extracellular matrix proteins]]
[[Category:Extracellular matrix proteins]]

Latest revision as of 14:49, 18 January 2019

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File:The Modular Structure of Fibronectin and its Binding Domains.png
The modular structure of fibronectin and its binding domains

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

Fibronectin exists as a protein 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]

  • soluble plasma fibronectin (formerly called "cold-insoluble globulin", or CIg) is a major protein component of blood plasma (300 μg/ml) and is produced in the liver by hepatocytes.
  • insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by various cells, primarily fibroblasts, as a soluble protein dimer and is then assembled into an insoluble matrix in a complex cell-mediated process.

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]

Structure

Fibronectin exists as a protein dimer, consisting of two nearly identical polypeptide chains linked by a pair of C-terminal disulfide bonds.[3] Each fibronectin subunit 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 resulting in a Beta-sandwich; however, type I and type II are stabilized by intra-chain disulfide bonds, while type III modules do not contain any disulfide bonds. 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 protomer. 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 association 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]

Function

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][7] 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 the binding of α4β1 integrin-expressing cells, 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.[8] 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.[9]

Fibronectin is also found in normal human saliva, which helps prevent colonization of the oral cavity and pharynx by potentially pathogenic bacteria.[10]

Matrix assembly

Cellular fibronectin is assembled into an insoluble fibrillar matrix in a complex cell-mediated process.[11] 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 aid 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 molecule. 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.


A transmembrane protein, CD93, has been shown to be essential for fibronectin matrix assembly (fibrillogenesis) in human dermal blood endothelial cells.[12] As a consequence, knockdown of CD93 in these cells resulted in the disruption of the fibronectin fibrillogenesis. Moreover, the CD93 knockout mice retinas displayed disrupted fibronectin matrix at the retinal sprouting front.[12]

Role in cancer

Several morphological changes has been observed in tumors and tumor-derived cell lines that have been attributed to decreased fibronectin expression, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, such as α5β1 integrins.[13]

Fibronectin has been implicated in carcinoma development.[14] 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 1 acts as a potential biomarker for radioresistance.[15]

FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.[16][17]

Role in wound healing

Fibronectin has profound effects on wound healing, including the formation of proper substratum for migration and growth of cells during the development and organization of granulation tissue, as well as remodeling and resynthesis of the connective tissue matrix.[18] The biological significance of fibronectin in vivo was studied during the mechanism of wound healing.[18] Plasma fibronectin levels are decreased in acute inflammation or following surgical trauma and in patients with disseminated intravascular coagulation.[19]

Fibronectin is located in the extracellular matrix of embryonic and adult tissues (not in the basement membranes of the adult tissues), but may be more widely distributed in inflammatory lesions. During blood clotting, the fibronectin remains associated with the clot, covalently cross-linked to fibrin with the help of Factor XIII (fibrin-stabilizing factor).[20][21] Fibroblasts play a major role in wound healing by adhering to fibrin. Fibroblast adhesion to fibrin requires fibronectin, and was strongest when the fibronectin was cross-linked to the fibrin. Patients with Factor XIII deficiencies display impairment in wound healing as fibroblasts don't grow well in fibrin lacking Factor XIII. Fibronectin promotes particle phagocytosis by both macrophages and fibroblasts. Collagen deposition at the wound site by fibroblasts takes place with the help of fibronectin. Fibronectin was also observed to be closely associated with the newly deposited collagen fibrils. Based on the size and histological staining characteristics of the fibrils, it is likely that at least in part they are composed of type III collagen (reticulin). An in vitro study with native collagen demonstrated that fibronectin binds to type III collagen rather than other types.[22]

In vivo vs in vitro

Plasma fibronectin, which is synthesized by hepatocytes,[23] and fibronectin synthesized by cultured fibroblasts are similar but not identical; immunological, structural, and functional differences have been reported.[24] It is likely that these differences result from differential processing of a single nascent mRNA. Nevertheless, plasma fibronectin can be insolubilized into the tissue extracellular matrix in vitro and in vivo. Both plasma and cellular fibronectins in the matrix form high molecular weight, disulfide-bonded multimers. The mechanism of formation of these multimers is not presently known. Plasma fibronectin has been shown to contain two free sulfhydryls per subunit (X), and cellular fibronectin has been shown to contain at least one. These sulfhydryls probably are buried within the tertiary structure, because sulfhydryls are exposed when the fibronectin is denatured. Such denaturation results in the oxidation of free sulfhydryls and formation of disulfide-bonded fibronectin multimers. This has led to speculation that the free sulfhydryls may be involved in formation of disulfide-bonded fibronectin multimers in the extracellular matrix. Consistent with this, sulfhydryl modification of fibronectin with N-ethylmaleimide prevents binding to cell layers. Tryptic cleavage patterns of multimeric fibronectin do not reveal the disulfide-bonded fragments that would be expected if multimerization involved one or both of the free sulfhydryls. The free sulfhydryls of fibronectin are not required for the binding of fibronectin to the cell layer or for its subsequent incorporation into the extracellular matrix. Disulfide-bonded multimerization of fibronectin in the cell layer occurs by disulfide bond exchange in the disulfide-rich amino-terminal one-third of the molecule.[24]

Interactions

Besides integrin, fibronectin binds to many other host and non-host molecules. For example, it has been shown to interact with proteins such fibrin, tenascin, TNF-α, BMP-1, rotavirus NSP-4, and many fibronectin-binding proteins from bacteria (like FBP-A; FBP-B on the N-terminal domain), as well as the glycosaminoglycan, heparan sulfate.

Fibronectin has been shown to interact with:

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Pankov R, Yamada KM (Oct 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. PMC 2748963. PMID 18451144.
  3. ↑ 3.0 3.1 3.2 Mao Y, Schwarzbauer JE (Sep 2005). "Fibronectin fibrillogenesis, a cell-mediated matrix assembly process". 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 (Dec 1997). "Modulatory roles for integrin activation and the synergy site of fibronectin during matrix assembly". Molecular Biology of the Cell. 8 (12): 2563–73. doi:10.1091/mbc.8.12.2563. PMC 25728. PMID 9398676.
  6. ↑ Grinnell F (1984). "Fibronectin and wound healing". Journal of Cellular Biochemistry. 26 (2): 107–116. doi:10.1002/jcb.240260206. PMID 6084665.
  7. ↑ Valenick LV, Hsia HC, Schwarzbauer JE (Sep 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.
  8. ↑ George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO (Dec 1993). "Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin". Development. 119 (4): 1079–91. PMID 8306876.
  9. ↑ Darribère T, Schwarzbauer JE (Apr 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.
  10. ↑ Hasty DL, Simpson WA (Sep 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. PMC 260663. PMID 3305363.
  11. ↑ Wierzbicka-Patynowski I, Schwarzbauer JE (Aug 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.
  12. ↑ 12.0 12.1 Lugano R, Vemuri K, Yu D, Bergqvist M, Smits A, Essand M, Johansson S, Dejana E, Dimberg A (August 2018). "CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis". The Journal of Clinical Investigation. 128 (8): 3280–3297. doi:10.1172/JCI97459. PMC 6063507. PMID 29763414.
  13. ↑ Hynes, Richard O. (1990). Fibronectins. Berlin: Springer-Verlag. ISBN 0-387-97050-9.
  14. ↑ Han S, Khuri FR, Roman J (Jan 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.
  15. ↑ Jerhammar F, Ceder R, Garvin S, Grénman R, Grafström RC, Roberg K (Dec 2010). "Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma". Cancer Biology & Therapy. 10 (12): 1244–1251. doi:10.4161/cbt.10.12.13432. PMID 20930522.
  16. ↑ Wasserman JK, Purgina B, Lai CK, Gravel D, Mahaffey A, Bell D, Chiosea SI (Jan 2016). "Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis". Head and Neck Pathology. 10: 279–85. doi:10.1007/s12105-015-0678-1. PMC 4972751. PMID 26759148.
  17. ↑ Lee JC, Jeng YM, Su SY, Wu CT, Tsai KS, Lee CH, Lin CY, Carter JM, Huang JW, Chen SH, Shih SR, Mariño-Enríquez A, Chen CC, Folpe AL, Chang YL, Liang CW (Mar 2015). "Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour". The Journal of Pathology. 235 (4): 539–45. doi:10.1002/path.4465. PMID 25319834.
  18. ↑ 18.0 18.1 Grinnell F, Billingham RE, Burgess L (Mar 1981). "Distribution of fibronectin during wound healing in vivo". The Journal of Investigative Dermatology. 76 (3): 181–189. doi:10.1111/1523-1747.ep12525694. PMID 7240787.
  19. ↑ Bruhn HD, Heimburger N (1976). "Factor-VIII-related antigen and cold-insoluble globulin in leukemias and carcinomas". Haemostasis. 5 (3): 189–192. doi:10.1159/000214134. PMID 1002003.
  20. ↑ Mosher DF (Aug 1975). "Cross-linking of cold-insoluble globulin by fibrin-stabilizing factor". The Journal of Biological Chemistry. 250 (16): 6614–6621. PMID 1158872.
  21. ↑ Mosher DF (Mar 1976). "Action of fibrin-stabilizing factor on cold-insoluble globulin and alpha2-macroglobulin in clotting plasma". The Journal of Biological Chemistry. 251 (6): 1639–1645. PMID 56335.
  22. ↑ Engvall E, Ruoslahti E, Miller EJ (Jun 1978). "Affinity of fibronectin to collagens of different genetic types and to fibrinogen". The Journal of Experimental Medicine. 147 (6): 1584–1595. doi:10.1084/jem.147.6.1584. PMC 2184308. PMID 567240.
  23. ↑ Tamkun JW, Hynes RO (Apr 1983). "Plasma fibronectin is synthesized and secreted by hepatocytes". The Journal of Biological Chemistry. 258 (7): 4641–7. PMID 6339502.
  24. ↑ 24.0 24.1 McKeown-Longo PJ, Mosher DF (Oct 1984). "Mechanism of formation of disulfide-bonded multimers of plasma fibronectin in cell layers of cultured human fibroblasts". The Journal of Biological Chemistry. 259 (19): 12210–12215. PMID 6480605.
  25. ↑ Jalkanen S, Jalkanen M (Feb 1992). "Lymphocyte CD44 binds the COOH-terminal heparin-binding domain of fibronectin". The Journal of Cell Biology. 116 (3): 817–25. doi:10.1083/jcb.116.3.817. PMC 2289325. PMID 1730778.
  26. ↑ Lapiere JC, Chen JD, Iwasaki T, Hu L, Uitto J, Woodley DT (Nov 1994). "Type VII collagen specifically binds fibronectin via a unique subdomain within the collagenous triple helix". The Journal of Investigative Dermatology. 103 (5): 637–41. doi:10.1111/1523-1747.ep12398270. PMID 7963647.
  27. ↑ Chen M, Marinkovich MP, Veis A, Cai X, Rao CN, O'Toole EA, Woodley DT (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". The Journal of Biological Chemistry. 272 (23): 14516–22. doi:10.1074/jbc.272.23.14516. PMID 9169408.
  28. ↑ Salonen EM, Jauhiainen M, Zardi L, Vaheri A, Ehnholm C (Dec 1989). "Lipoprotein(a) binds to fibronectin and has serine proteinase activity capable of cleaving it". The EMBO Journal. 8 (13): 4035–40. PMC 401578. PMID 2531657.
  29. ↑ Martin JA, Miller BA, Scherb MB, Lembke LA, Buckwalter JA (Jul 2002). "Co-localization of insulin-like growth factor binding protein 3 and fibronectin in human articular cartilage". Osteoarthritis and Cartilage / OARS, Osteoarthritis Research Society. 10 (7): 556–63. doi:10.1053/joca.2002.0791. PMID 12127836.
  30. ↑ Gui Y, Murphy LJ (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". The Journal of Clinical Endocrinology and Metabolism. 86 (5): 2104–10. doi:10.1210/jcem.86.5.7472. PMID 11344214.
  31. ↑ Chung CY, Zardi L, Erickson HP (Dec 1995). "Binding of tenascin-C to soluble fibronectin and matrix fibrils". The Journal of Biological Chemistry. 270 (48): 29012–7. doi:10.1074/jbc.270.48.29012. PMID 7499434.
  32. ↑ Zhou Y, Li L, Liu Q, Xing G, Kuai X, Sun J, Yin X, Wang J, Zhang L, He F (May 2008). "E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3". Cellular Signalling. 20 (5): 942–8. doi:10.1016/j.cellsig.2008.01.010. PMID 18276110.

Further reading

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