Fascin

2017-08-04T19:29:58Z

188.4.242.79: /* Function */

{{infobox protein
| Name = [[FSCN1|fascin homolog 1]]
| caption = [[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of dimeric human fascin 1.<ref name="pmid20434460">{{PDB|1DFC}}; {{cite journal | vauthors = Sedeh RS, Fedorov AA, Fedorov EV, Ono S, Matsumura F, Almo SC, Bathe M | title = Structure, evolutionary conservation, and conformational dynamics of Homo sapiens fascin-1, an F-actin crosslinking protein | journal = J. Mol. Biol. | volume = 400 | issue = 3 | pages = 589–604 |date=July 2010 | pmid = 20434460 | doi = 10.1016/j.jmb.2010.04.043 | url = | issn = }}</ref>
| image = Fascin.pdb.png
| width =
| HGNCid = 11148
| Symbol = [[FSCN1]]
| AltSymbols = SNL
| EntrezGene = 6624
| OMIM = 602689
| RefSeq = NM_003088
| UniProt = Q16658
| PDB =
| ECnumber =
| Chromosome = 7
| Arm = p
| Band = 22
| LocusSupplementaryData =
}}
{{infobox protein
| Name = [[FSCN2|fascin homolog, retinal]]
| caption =
| image =
| width =
| HGNCid = 3960
| Symbol = [[FSCN2]]
| AltSymbols =
| EntrezGene = 25794
| OMIM = 607643
| RefSeq = NM_012418
| UniProt = O14926
| PDB =
| ECnumber =
| Chromosome = 17
| Arm = q
| Band = 25
| LocusSupplementaryData =
}}
{{infobox protein
| Name = [[FSCN3|fascin homolog 3, testicular]]
| caption =
| image =
| width =
| HGNCid = 3961
| Symbol = [[FSCN3]]
| AltSymbols =
| EntrezGene = 29999
| OMIM =
| RefSeq = NM_020369
| UniProt = Q9NQT6
| PDB =
| ECnumber =
| Chromosome = 7
| Arm = q
| Band = 31.3
| LocusSupplementaryData =
}}
'''Fascin''' is an [[actin]] bundling [[protein]].

== Species and tissue distribution ==

It is a 54-58 [[kilodalton]] monomeric [[actin]] filament bundling protein originally isolated from [[sea urchin]] egg but also found in ''[[Drosophila]]''<ref>{{cite journal | vauthors = Bryan J, Edwards R, Matsudaira P, Otto J, Wulfkuhle J | title = Fascin, an echinoid actin-bundling protein, is a homolog of the Drosophila singed gene product | journal = [[Proceedings of the National Academy of Sciences of the United States of America]] | volume = 90 | issue = 19 | pages = 9115–9119 | date = October 1993 | pmid = 8415664 | pmc = 47512 | doi = 10.1073/pnas.90.19.9115 | issn = 0027-8424 }}</ref> and vertebrates,<ref>{{cite journal | vauthors = Edwards RA, Bryan J | title = Fascins, a family of actin bundling proteins | journal = [[Cell Motility and the Cytoskeleton]] | volume = 32 | issue = 1 | pages = 1–9 | year = 1995 | pmid = 8674129 | doi = 10.1002/cm.970320102 | publisher = [[John Wiley & Sons]] | issn = 0886-1544 }}</ref> including humans.<ref>{{cite journal | vauthors = Yamashiro-Matsumura S, Matsumura F | title = Purification and characterization of an F-actin-bundling 55-kilodalton protein from HeLa cells | journal = [[Journal of Biological Chemistry]] | volume = 260 | issue = 8 | pages = 5087–5097 | date = April 1985 | pmid = 3886649 | issn = 0021-9258 }}</ref> Fascin (from the Latin for ''bundle'') is spaced at 11 nanometre intervals along the [[Protein filament|filament]]. The bundles in cross section are seen to be hexagonally packed, and the longitudinal spacing is compatible with a model where fascin [[cross-link]]s at alternating 4 and 5 actins.<ref>{{cite journal | vauthors = Bryan J, Kane RE | title = Separation and interaction of the major components of sea urchin actin gel | journal = [[Journal of Molecular Biology]] | volume = 125 | issue = 2 | pages = 207–224 | date = October 1978 | pmid = 731692 | doi = 10.1016/0022-2836(78)90345-5 | issn = 0022-2836 }}</ref> It is calcium insensitive and [[monomer]]ic. Three forms of fascin are found in vertebrates: Fascin1, widely found in the nervous system and elsewhere; fascin2 found in the [[retina]]l [[photoreceptor cell]]s; fascin3, which is only found in the [[testes]].<ref name="ReferenceA">{{cite journal | vauthors = Adams JC | title = Roles of fascin in cell adhesion and motility | journal = [[Current Opinion in Cell Biology]] | volume = 16 | issue = 5 | pages = 590–596 | date = October 2004 | pmid = 15363811 | pmc = | doi = 10.1016/j.ceb.2004.07.009 | publisher = | issn = 0955-0674 | bibcode = | oclc = }}</ref><ref name="Elsevier">{{cite journal | vauthors = Hashimoto Y, Skacel M, Adams JC | title = Roles of fascin in human carcinoma motility and signaling: Prospects for a novel biomarker? | journal = The International Journal of Biochemistry & Cell Biology | volume = 37 | issue = 9 | pages = 1787–1804 | date = September 2005 | pmid = 16002322 | doi = 10.1016/j.biocel.2005.05.004 | publisher = [[Elsevier]] | issn = 1357-2725 }}</ref>

== Function ==

Fascin binds [[beta-catenin]],<ref>{{cite journal | vauthors = Tao YS, Edwards RA, Tubb B, Wang S, Bryan J, McCrea PD | title = beta-Catenin associates with the actin-bundling protein fascin in a noncadherin complex | journal = Journal of Cell Biology | volume = 134 | issue = 5 | pages = 1271–1281 | date = September 1996 | pmid = 8794867 | pmc = 2120989 | doi = 10.1083/jcb.134.5.1271 | publisher = [[Rockefeller University Press]] | issn = 0021-9525 }}</ref> and colocalizes with it at the leading edges and borders of [[epithelial]] and [[endothelial]] cells. The role of Fascin in regulating [[cytoskeletal]] structures for the maintenance of [[cell adhesion]], coordinating [[motility]] and [[cellular infiltration|invasion]] through interactions with [[signalling pathway]]s is an active area of research especially from the [[cancer]] biology perspective.<ref name="ReferenceA"/><ref name="Elsevier"/> Fascin localizes to actin-rich protrusions at the cell surface called filopodia. Recent study shows that fascin also localizes to [[invadopodia]], membrane protrusions formed at the adherent cell surface that facilitate extracellular matrix (ECM) invasion, this provide a potential molecular mechanism for how fascin increases the invasiveness of cancer cells since fascin expression is upregulated in a spectrum of cancers.<ref>{{cite journal | vauthors = Li A, Dawson JC, Forero-Vargas M, Spence HJ, Yu X, König I, Anderson K, Machesky LM | title = The actin-bundling protein fascin stabilizes actin in invadopodia and potentiates protrusive invasion | journal = Curr. Biol. | volume = 20 | issue = 4 | pages = 339–45 | date = Feb 2010 | pmid = 20137952 | doi = 10.1016/j.cub.2009.12.035 | issn = | pmc=3163294}}</ref> Studies have also shown that Fascin plays a major role in immune suppression. T regulatory cell adhesion to antigen presenting dendritic cell causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1–dependent actin polarization in antigen presenting dendritic cells toward the T reg cell adhesion zone. Although it is reversible upon T regulatory cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of dendritic cells, leading to reduced T cell priming. This suggests Treg-mediated suppression of antigen presenting cells is a multi-step process. In addition to CTLA-4 CD80/CD86 interaction fascin dependent polarization of cytoskeleton towards dendritic cell Treg immune synapse play a pivotal role.<ref>{{Cite journal| doi = 10.1084/jem.20160620| issn = 0022-1007 | eissn = 1540-9538| pages = –20160620| last1 = Chen| first1 = Jiahuan| last2 = Ganguly| first2 = Anutosh| last3 = Mucsi| first3 = Ashley D.| last4 = Meng| first4 = Junchen| last5 = Yan| first5 = Jiacong| last6 = Detampel| first6 = Pascal| last7 = Munro| first7 = Fay| last8 = Zhang| first8 = Zongde| last9 = Wu| first9 = Mei| last10 = Hari| first10 = Aswin| last11 = Stenner| first11 = Melanie D.| last12 = Zheng| first12 = Wencheng| last13 = Kubes| first13 = Paul| last14 = Xia| first14 = Tie| last15 = Amrein| first15 = Matthias W.| last16 = Qi| first16 = Hai| last17 = Shi| first17 = Yan| title = Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy| journal = Journal of Experimental Medicine| date = 2017-01-12| url = http://jem.rupress.org/content/early/2017/01/11/jem.20160620| pmid = 28082358| pmc=5294852| volume=214}}</ref> In normal tissue, inflammation and the immune response would be limited by secretion of TGF-β. TGF-β on the one hand induces fascin expression, but on the other hand, restricts activity of transcription factor NF-κB. This results to limited fascin expression and allows tissue to rebuild epithelial barriers. In cancer, instead, TGF-β does not restrict NF-κB activity, and both can increase fascin expression, disrupting tissue structure and function. <ref>{{cite journal|last1=Vlahopoulos|first1=SA|last2=Cen|first2=O|last3=Hengen|first3=N|last4=Agan|first4=J|last5=Moschovi|first5=M|last6=Critselis|first6=E|last7=Adamaki|first7=M|last8=Bacopoulou|first8=F|last9=Copland|first9=JA|last10=Boldogh|first10=I|last11=Karin|first11=M|last12=Chrousos|first12=GP|title=Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment.|journal=Cytokine & Growth Factor Reviews|date=20 June 2015|pmid=26119834|doi=10.1016/j.cytogfr.2015.06.001|volume=26|pages=389–403|pmc=4526340}}</ref>

== Clinical significance ==

Abnormal fascin [[gene expression|expression]] or function has been implicated in [[breast cancer]],<ref>{{cite journal | vauthors = Grothey A, Hashizume R, Sahin AA, McCrea PD | title = Fascin, an actin-bundling protein associated with cell motility, is upregulated in hormone receptor negative breast cancer | journal = [[British Journal of Cancer]] | volume = 83 | issue = 7 | pages = 870–873 | year = 2000 | pmid = 10970687 | pmc = 2374674 | doi = 10.1054/bjoc.2000.1395 | issn = 0007-0920 }}</ref> [[colon cancer]],<ref>{{cite journal | vauthors = Jawhari AU, Buda A, Jenkins M, Shehzad K, Sarraf C, Noda M, Farthing MJ, Pignatelli M, Adams JC | title = Fascin, an actin-bundling protein, modulates colonic epithelial cell invasiveness and differentiation in vitro | journal = American Journal of Pathology | volume = 162 | issue = 1 | pages = 69–80 | date = January 2003 | pmid = 12507891 | pmc = 1851132 | doi = 10.1016/S0002-9440(10)63799-6 | publisher = American Society for Investigative Pathology | issn = 0002-9440 }}</ref><ref>{{cite journal | vauthors = Vignjevic D, Schoumacher M, Gavert N, Janssen KP, Jih G, Laé M, Louvard D, Ben-Ze'ev A, Robine S | title = Fascin, a Novel Target of ß-Catenin-TCF Signaling, Is Expressed at the Invasive Front of Human Colon Cancer | journal = [[Cancer Research (journal)|Cancer Research]] | volume = 67 | issue = 14 | pages = 6844–6853 | date = July 2007 | pmid = 17638895 | doi = 10.1158/0008-5472.CAN-07-0929 | issn = 0008-5472 }}</ref> esophageal [[squamous cell carcinoma]],<ref>{{cite journal | vauthors = Hashimoto Y, Ito T, Inoue H, Okumura T, Tanaka E, Tsunoda S, Higashiyama M, Watanabe G, Imamura M, Shimada Y | title = Prognostic Significance of Fascin Overexpression in Human Esophageal Squamous Cell Carcinoma | journal = Clinical Cancer Research | volume = 11 | issue = 7 | pages = 2597–2605 | date = April 2005 | pmid = 15814639 | doi = 10.1158/1078-0432.CCR-04-1378 | publisher = [[American Association for Cancer Research]] | issn = 1078-0432 }}</ref> [[gallbladder cancer]],<ref>{{cite journal | vauthors = Roh YH, Kim YH, Choi HJ, Lee KE, Roh MS | title = Fascin overexpression correlates with positive thrombospondin-1 and syndecan-1 expressions and a more aggressive clinical course in patients with gallbladder cancer | journal = Journal of Hepatobiliary Pancreatic Surgery | volume = 16 | issue = 3 | pages = 315–21 | date = March 2009 | pmid = 19259612 | doi = 10.1007/s00534-009-0046-1 | publisher = [[Springer Science+Business Media|Springer International]] | issn = 0944-1166 }}</ref> [[pancreatic cancer]],<ref name="LiMorton2014">{{cite journal | vauthors = Li A, Morton JP, Ma Y, Karim SA, Zhou Y, Faller WJ, Woodham EF, Morris HT, Stevenson RP, Juin A, Jamieson NB, MacKay CJ, Carter CR, Leung HY, Yamashiro S, Blyth K, Sansom OJ, Machesky LM | title = Fascin Is Regulated by Slug, Promotes Progression of Pancreatic Cancer in Mice, and Is Associated With Patient Outcomes | journal = Gastroenterology | volume = 146 | issue = 5 | pages = 1386–1396.e17 | year = 2014 | pmid = 24462734 | doi = 10.1053/j.gastro.2014.01.046 | issn = 0016-5085 | pmc=4000441}}</ref> and [[prostate cancer]].<ref>{{cite journal | vauthors = Darnel AD, Behmoaram E, Vollmer RT, Corcos J, Bijian K, Sircar K, Su J, Jiao J, Alaoui-Jamali MA, Bismar TA | title = Fascin regulates prostate cancer cell invasion and is associated with metastasis and biochemical failure in prostate cancer | journal = Clinical Cancer Research | volume = 15 | issue = 4 | pages = 1376–1383 | date = February 2009 | pmid = 19228738 | doi = 10.1158/1078-0432.CCR-08-1789 | publisher = [[American Association for Cancer Research]] | issn = 1078-0432 }}</ref> It is also helpful in identifying Hodgkin cells.

== Structure ==

Fascin is a structural protein found in mesenchyme, nervous, and retinal tissue and is used in the bundling of [[actin]] molecules.<ref name="pmid20601080">{{cite journal | vauthors = Jayo A, Parsons M | title = Fascin: a key regulator of cytoskeletal dynamics | journal = Int. J. Biochem. Cell Biol. | volume = 42 | issue = 10 | pages = 1614–7 | date = October 2010 | pmid = 20601080 | doi = 10.1016/j.biocel.2010.06.019 | url = | issn = }}</ref>

The structure of human fascin has been determined to a resolution of 1.8 Å (PDBID 3LLP) and reveals an arrangement of four tandem [[beta-trefoil domain]]s that form a two lobed structure with pseudo 2-fold symmetry. It is stabilized by a [[hydrophobe|hydrophobic]] core and a [[hydrophile|hydrophilic]] surface since it is often found inside cell [[cytoplasm]] in the formation of [[filopodia]].<ref name="pmid20434460"/>

== References ==
{{reflist|35em}}

== External links ==
* {{MeshName|fascin}}

[[Category:Proteins]]

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Fascin