CDH1 (gene): Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''Cadherin-1''' also known as '''CAM 120/80''' or '''epithelial cadherin''' (E-cadherin) or '''uvomorulin''' is a [[protein]] that in humans is encoded by the ''CDH1'' [[gene]].<ref name="pmid9925936">{{cite journal |vauthors=Huntsman DG, Caldas C | title = Assignment1 of the E-cadherin gene (CDH1) to chromosome 16q22.1 by radiation hybrid mapping | journal = Cytogenet Cell Genet | volume = 83 | issue = 1–2 | pages = 82–3 |date=Mar 1999 | pmid = 9925936 | pmc =  | doi =10.1159/000015134 }}</ref> CDH1 has also been designated as '''CD324''' ([[cluster of differentiation]] 324). It is a [[tumor suppressor gene]].<ref name="pmid9837810">{{cite journal |vauthors=Semb H, Christofori G |title=The tumor-suppressor function of E-cadherin |journal=Am. J. Hum. Genet. |volume=63 |issue=6 |pages=1588–93 |date=December 1998 |pmid=9837810 |pmc=1377629 |doi=10.1086/302173 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61602-4}}</ref><ref name="pmid12810698">{{cite journal |vauthors=Wong AS, Gumbiner BM |title=Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin |journal=J. Cell Biol. |volume=161 |issue=6 |pages=1191–203 |date=June 2003 |pmid=12810698 |pmc=2173007 |doi=10.1083/jcb.200212033 |url=http://www.jcb.org/cgi/pmidlookup?view=long&pmid=12810698}}</ref>
'''Cadherin-1''' also known as '''CAM 120/80''' or '''epithelial cadherin''' (E-cadherin) or '''uvomorulin''' is a [[protein]] that in humans is encoded by the ''CDH1'' [[gene]].<ref name="pmid9925936">{{cite journal | vauthors = Huntsman DG, Caldas C | title = Assignment1 of the E-cadherin gene (CDH1) to chromosome 16q22.1 by radiation hybrid mapping | journal = Cytogenetics and Cell Genetics | volume = 83 | issue = 1-2 | pages = 82–3 | date = Mar 1999 | pmid = 9925936 | pmc =  | doi = 10.1159/000015134 }}</ref> CDH1 has also been designated as '''CD324''' ([[cluster of differentiation]] 324). It is a [[tumor suppressor gene]].<ref name="pmid9837810">{{cite journal | vauthors = Semb H, Christofori G | title = The tumor-suppressor function of E-cadherin | journal = American Journal of Human Genetics | volume = 63 | issue = 6 | pages = 1588–93 | date = December 1998 | pmid = 9837810 | pmc = 1377629 | doi = 10.1086/302173 | url = http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61602-4 }}</ref><ref name="pmid12810698">{{cite journal | vauthors = Wong AS, Gumbiner BM | title = Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin | journal = The Journal of Cell Biology | volume = 161 | issue = 6 | pages = 1191–203 | date = June 2003 | pmid = 12810698 | pmc = 2173007 | doi = 10.1083/jcb.200212033 | url = http://www.jcb.org/cgi/pmidlookup?view=long&pmid=12810698 }}</ref>


== Function ==
== Function ==


Cadherin-1 is a classical member of the [[cadherin]] superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved [[Cadherin cytoplasmic region|cytoplasmic tail]]. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells, and the cytoplasmic domain is required for internalization. Identified transcript variants arise from mutation at consensus splice sites.<ref>{{cite web | title = Entrez Gene: CDH1 cadherin 1, type 1, E-cadherin (epithelial)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=999| accessdate = }}</ref>
Cadherin-1 is a classical member of the [[cadherin]] superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved [[Cadherin cytoplasmic region|cytoplasmic tail]]. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells, and the cytoplasmic domain is required for internalization. Identified transcript variants arise from mutation at consensus splice sites.<ref>{{cite web | title = Entrez Gene: CDH1 cadherin 1, type 1, E-cadherin (epithelial)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=999| access-date = }}</ref>


E-cadherin ([[epithelium|epithelial]]) is the most well-studied member of the [[cadherin]] family. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds [[p120-catenin]] and [[beta-catenin]]. The [[intracellular domain]] contains a highly-[[phosphorylation|phosphorylated]] region vital to beta-catenin binding and, therefore, to E-cadherin function.{{Citation needed|date=December 2008}} Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of [[actin]]-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the [[cytoskeleton]].
E-cadherin ([[epithelium|epithelial]]) is the most well-studied member of the [[cadherin]] family. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds [[p120-catenin]] and [[beta-catenin]]. The [[intracellular domain]] contains a highly-[[phosphorylation|phosphorylated]] region vital to beta-catenin binding and, therefore, to E-cadherin function.{{Citation needed|date=December 2008}} Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of [[actin]]-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the [[cytoskeleton]].


E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction.{{Citation needed|date=December 2008}} In adult tissues, E-cadherin is expressed in [[epithelial]] tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface. {{Citation needed|date=December 2008}}  Cell-cell interactions mediated by E-cadherin are crucial to [[blastula]] formation in many animals.<ref name=Fleming>{{cite journal |vauthors=Fleming TP, Papenbrock T, Fesenko I, Hausen P, Sheth B | title = Assembly of tight junctions during early vertebrate development | journal = Semin. Cell Dev. Biol. | volume = 11 | issue = 4 | pages = 291–9 |date=August 2000 | pmid = 10966863 | doi = 10.1006/scdb.2000.0179 }}</ref>
E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction.{{Citation needed|date=December 2008}} In adult tissues, E-cadherin is expressed in [[epithelial]] tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface. {{Citation needed|date=December 2008}}  Cell-cell interactions mediated by E-cadherin are crucial to [[blastula]] formation in many animals.<ref name=Fleming>{{cite journal | vauthors = Fleming TP, Papenbrock T, Fesenko I, Hausen P, Sheth B | title = Assembly of tight junctions during early vertebrate development | journal = Seminars in Cell & Developmental Biology | volume = 11 | issue = 4 | pages = 291–9 | date = August 2000 | pmid = 10966863 | doi = 10.1006/scdb.2000.0179 }}</ref>


== Clinical significance ==
== Clinical significance ==


Loss of E-cadherin function or expression has been implicated in [[cancer]] progression and [[metastasis]].<ref>{{cite journal|last1=Beavon|first1=IR|title=The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation.|journal=European Journal of Cancer|date=August 2000|volume=36|issue=13 Spec No|pages=1607–20|pmid=10959047|doi=10.1016/S0959-8049(00)00158-1}}</ref><ref name=weincancer>{{cite book|last=Weinberg|first=Robert|title=The Biology of Cancer|year=2006|publisher=Garland Science|isbn=9780815340782|pages=864 pages|url=http://www.garlandscience.com/product/isbn/9780815340782}}</ref>  E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the [[basement membrane]] and invade surrounding tissues.<ref name="weincancer"/> E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive [[mammary ductal carcinoma|ductal carcinoma]], E-cadherin expression is markedly reduced or absent in the great majority of [[invasive lobular carcinoma]]s when studied by [[immunohistochemistry]].<ref>Rosen, P. Rosen's Breast Pathology, 3rd ed, 2009, p. 704. Lippincott Williams & Wilkins.</ref>
Loss of E-cadherin function or expression has been implicated in [[cancer]] progression and [[metastasis]].<ref>{{cite journal | vauthors = Beavon IR | title = The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation | journal = European Journal of Cancer | volume = 36 | issue = 13 Spec No | pages = 1607–20 | date = August 2000 | pmid = 10959047 | doi = 10.1016/S0959-8049(00)00158-1 }}</ref><ref name=weincancer>{{cite book|last=Weinberg|first=Robert|title=The Biology of Cancer|year=2006|publisher=Garland Science|isbn=9780815340782|pages=864 pages|url=http://www.garlandscience.com/product/isbn/9780815340782}}</ref>  E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the [[basement membrane]] and invade surrounding tissues.<ref name="weincancer"/> E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive [[mammary ductal carcinoma|ductal carcinoma]], E-cadherin expression is markedly reduced or absent in the great majority of [[invasive lobular carcinoma]]s when studied by [[immunohistochemistry]].<ref>Rosen, P. Rosen's Breast Pathology, 3rd ed, 2009, p. 704. Lippincott Williams & Wilkins.</ref>
 
== Interactions ==


==Interactions==
CDH1 (gene) has been shown to [[Protein-protein interaction|interact]] with  
CDH1 (gene) has been shown to [[Protein-protein interaction|interact]] with  
{{div col|colwidth=30em}}
{{div col|colwidth=30em}}


* [[CBLL1]],<ref name="prid11836526">{{Cite journal  
* [[CBLL1]],<ref name="prid11836526">{{cite journal | vauthors = Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HE, Behrens J, Sommer T, Birchmeier W | title = Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex | journal = Nature Cell Biology | volume = 4 | issue = 3 | pages = 222–31 | date = March 2002 | pmid = 11836526 | pmc = | doi = 10.1038/ncb758 }}</ref>
|vauthors=Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HE, Behrens J, Sommer T, Birchmeier W | doi = 10.1038/ncb758
* [[CDC27]],<ref name="pmid12956947">{{cite journal | vauthors = Vodermaier HC, Gieffers C, Maurer-Stroh S, Eisenhaber F, Peters JM | title = TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1 | journal = Current Biology | volume = 13 | issue = 17 | pages = 1459–68 | date = September 2003 | pmid = 12956947 | doi = 10.1016/S0960-9822(03)00581-5 }}</ref>
| title = Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex  
| journal = Nature Cell Biology  
| volume = 4  
| issue = 3  
| pages = 222–231
| year = 2002  
| pmid = 11836526  
| pmc =  
}}</ref>
* [[CDC27]],<ref name="pmid12956947">{{cite journal |vauthors=Vodermaier HC, Gieffers C, Maurer-Stroh S, Eisenhaber F, Peters JM | title = TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1 | journal = Curr. Biol. | volume = 13 | issue = 17 | pages = 1459–68 |date=September 2003 | pmid = 12956947 | doi = 10.1016/S0960-9822(03)00581-5 }}</ref>
* [[CDON]],<ref name=pmid12634428/>
* [[CDON]],<ref name=pmid12634428/>
* [[CDH3 (gene)|CDH3]],<ref name="pmid10910767">{{cite journal |vauthors=Klingelhöfer J, Troyanovsky RB, Laur OY, Troyanovsky S | title = Amino-terminal domain of classic cadherins determines the specificity of the adhesive interactions | journal = J. Cell Sci. | volume = 113 | issue = 16| pages = 2829–36 |date=August 2000 | pmid = 10910767 | doi =  }}</ref>
* [[CDH3 (gene)|CDH3]],<ref name="pmid10910767">{{cite journal | vauthors = Klingelhöfer J, Troyanovsky RB, Laur OY, Troyanovsky S | title = Amino-terminal domain of classic cadherins determines the specificity of the adhesive interactions | journal = Journal of Cell Science | volume = 113 ( Pt 16) | issue = 16 | pages = 2829–36 | date = August 2000 | pmid = 10910767 | doi =  }}</ref>
* [[C-Met]],<ref name="pmid11254878"/>
* [[C-Met]],<ref name="pmid11254878"/>
* [[CTNND1]],<ref name="pmid7651399">{{cite journal |vauthors=Daniel JM, Reynolds AB | title = The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or alpha-catenin | journal = Mol. Cell. Biol. | volume = 15 | issue = 9 | pages = 4819–24 |date=September 1995 | pmid = 7651399 | pmc = 230726 | doi = 10.1128/mcb.15.9.4819}}</ref><ref name="pmid12427869">{{cite journal |vauthors=Ireton RC, Davis MA, van Hengel J, Mariner DJ, Barnes K, Thoreson MA, Anastasiadis PZ, Matrisian L, Bundy LM, Sealy L, Gilbert B, van Roy F, Reynolds AB | title = A novel role for p120 catenin in E-cadherin function | journal = J. Cell Biol. | volume = 159 | issue = 3 | pages = 465–76 |date=November 2002 | pmid = 12427869 | pmc = 2173073 | doi = 10.1083/jcb.200205115 }}</ref><ref name=pmid7542250/><ref name=pmid9535896/><ref name="pmid12707304">{{cite journal |vauthors=Bonné S, Gilbert B, Hatzfeld M, Chen X, Green KJ, van Roy F | title = Defining desmosomal plakophilin-3 interactions | journal = J. Cell Biol. | volume = 161 | issue = 2 | pages = 403–16 |date=April 2003 | pmid = 12707304 | pmc = 2172904 | doi = 10.1083/jcb.200303036 }}</ref><ref name=pmid12640114/><ref name=pmid7876318/><ref name="pmid10409703">{{cite journal |vauthors=Ohkubo T, Ozawa M | title = p120(ctn) binds to the membrane-proximal region of the E-cadherin cytoplasmic domain and is involved in modulation of adhesion activity | journal = J. Biol. Chem. | volume = 274 | issue = 30 | pages = 21409–15 |date=July 1999 | pmid = 10409703 | doi = 10.1074/jbc.274.30.21409 }}</ref>
* [[CTNND1]],<ref name="pmid7651399">{{cite journal | vauthors = Daniel JM, Reynolds AB | title = The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or alpha-catenin | journal = Molecular and Cellular Biology | volume = 15 | issue = 9 | pages = 4819–24 | date = September 1995 | pmid = 7651399 | pmc = 230726 | doi = 10.1128/mcb.15.9.4819 }}</ref><ref name="pmid12427869">{{cite journal | vauthors = Ireton RC, Davis MA, van Hengel J, Mariner DJ, Barnes K, Thoreson MA, Anastasiadis PZ, Matrisian L, Bundy LM, Sealy L, Gilbert B, van Roy F, Reynolds AB | title = A novel role for p120 catenin in E-cadherin function | journal = The Journal of Cell Biology | volume = 159 | issue = 3 | pages = 465–76 | date = November 2002 | pmid = 12427869 | pmc = 2173073 | doi = 10.1083/jcb.200205115 }}</ref><ref name=pmid7542250/><ref name=pmid9535896/><ref name="pmid12707304">{{cite journal | vauthors = Bonné S, Gilbert B, Hatzfeld M, Chen X, Green KJ, van Roy F | title = Defining desmosomal plakophilin-3 interactions | journal = The Journal of Cell Biology | volume = 161 | issue = 2 | pages = 403–16 | date = April 2003 | pmid = 12707304 | pmc = 2172904 | doi = 10.1083/jcb.200303036 }}</ref><ref name=pmid12640114/><ref name=pmid7876318/><ref name="pmid10409703">{{cite journal | vauthors = Ohkubo T, Ozawa M | title = p120(ctn) binds to the membrane-proximal region of the E-cadherin cytoplasmic domain and is involved in modulation of adhesion activity | journal = The Journal of Biological Chemistry | volume = 274 | issue = 30 | pages = 21409–15 | date = July 1999 | pmid = 10409703 | doi = 10.1074/jbc.274.30.21409 }}</ref>
* [[Beta-catenin|CTNNB1]],<ref name="pmid12634428">{{cite journal |vauthors=Kang JS, Feinleib JL, Knox S, Ketteringham MA, Krauss RS | title = Promyogenic members of the Ig and cadherin families associate to positively regulate differentiation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 7 | pages = 3989–94 |date=April 2003 | pmid = 12634428 | pmc = 153035 | doi = 10.1073/pnas.0736565100 }}</ref><ref name="pmid11254878">{{cite journal |vauthors=Davies G, Jiang WG, Mason MD | title = HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells | journal = Int. J. Mol. Med. | volume = 7 | issue = 4 | pages = 385–8 |date=April 2001 | pmid = 11254878 | doi = 10.3892/ijmm.7.4.385}}</ref><ref name="pmid7542250">{{cite journal |vauthors=Kinch MS, Clark GJ, Der CJ, Burridge K | title = Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia | journal = J. Cell Biol. | volume = 130 | issue = 2 | pages = 461–71 |date=July 1995 | pmid = 7542250 | pmc = 2199929 | doi = 10.1083/jcb.130.2.461 }}</ref><ref name="pmid9535896">{{cite journal |vauthors=Hazan RB, Norton L | title = The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton | journal = J. Biol. Chem. | volume = 273 | issue = 15 | pages = 9078–84 |date=April 1998 | pmid = 9535896 | doi = 10.1074/jbc.273.15.9078 }}</ref><ref name="pmid12640114">{{cite journal |vauthors=Piedra J, Miravet S, Castaño J, Pálmer HG, Heisterkamp N, García de Herreros A, Duñach M | title = p120 Catenin-associated Fer and Fyn tyrosine kinases regulate beta-catenin Tyr-142 phosphorylation and beta-catenin-alpha-catenin Interaction | journal = Mol. Cell. Biol. | volume = 23 | issue = 7 | pages = 2287–97 |date=April 2003 | pmid = 12640114 | pmc = 150740 | doi = 10.1128/MCB.23.7.2287-2297.2003 }}</ref><ref name="pmid7876318">{{cite journal |vauthors=Shibamoto S, Hayakawa M, Takeuchi K, Hori T, Miyazawa K, Kitamura N, Johnson KR, Wheelock MJ, Matsuyoshi N, Takeichi M | title = Association of p120, a tyrosine kinase substrate, with E-cadherin/catenin complexes | journal = J. Cell Biol. | volume = 128 | issue = 5 | pages = 949–57 |date=March 1995 | pmid = 7876318 | pmc = 2120395 | doi = 10.1083/jcb.128.5.949 }}</ref><ref name="pmid11712088">{{cite journal |vauthors=Kucerová D, Sloncová E, Tuhácková Z, Vojtechová M, Sovová V | title = Expression and interaction of different catenins in colorectal carcinoma cells | journal = Int. J. Mol. Med. | volume = 8 | issue = 6 | pages = 695–8 |date=December 2001 | pmid = 11712088 | doi = 10.3892/ijmm.8.6.695}}</ref><ref name="pmid7954478">{{cite journal |vauthors=Oyama T, Kanai Y, Ochiai A, Akimoto S, Oda T, Yanagihara K, Nagafuchi A, Tsukita S, Shibamoto S, Ito F | title = A truncated beta-catenin disrupts the interaction between E-cadherin and alpha-catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines | journal = Cancer Res. | volume = 54 | issue = 23 | pages = 6282–7 |date=December 1994 | pmid = 7954478 | doi = }}</ref><ref name="pmid9405455">{{cite journal |vauthors=Hazan RB, Kang L, Roe S, Borgen PI, Rimm DL | title = Vinculin is associated with the E-cadherin adhesion complex | journal = J. Biol. Chem. | volume = 272 | issue = 51 | pages = 32448–53 |date=December 1997 | pmid = 9405455 | doi = 10.1074/jbc.272.51.32448 }}</ref><ref name="pmid12061792">{{cite journal |vauthors=Jiang MC, Liao CF, Tai CC | title = CAS/CSE 1 stimulates E-cadhrin-dependent cell polarity in HT-29 human colon epithelial cells | journal = Biochem. Biophys. Res. Commun. | volume = 294 | issue = 4 | pages = 900–5 |date=June 2002 | pmid = 12061792 | doi = 10.1016/S0006-291X(02)00551-X }}</ref><ref name="pmid11245482">{{cite journal |vauthors=Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A, Dunach M, Neckers LM | title = Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription | journal = Cancer Res. | volume = 61 | issue = 4 | pages = 1671–7 |date=February 2001 | pmid = 11245482 | doi = }}</ref><ref name="pmid9819408">{{cite journal |vauthors=Li Y, Bharti A, Chen D, Gong J, Kufe D | title = Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin | journal = Mol. Cell. Biol. | volume = 18 | issue = 12 | pages = 7216–24 |date=December 1998 | pmid = 9819408 | pmc = 109303 | doi = 10.1128/mcb.18.12.7216}}</ref><ref name="pmid15023525">{{cite journal |vauthors=Wendeler MW, Praus M, Jung R, Hecking M, Metzig C, Gessner R | title = Ksp-cadherin is a functional cell-cell adhesion molecule related to LI-cadherin | journal = Exp. Cell Res. | volume = 294 | issue = 2 | pages = 345–55 |date=April 2004 | pmid = 15023525 | doi = 10.1016/j.yexcr.2003.11.022 }}</ref><ref name="pmid12830000">{{cite journal |vauthors=Shibata T, Chuma M, Kokubu A, Sakamoto M, Hirohashi S | title = EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma | journal = Hepatology | volume = 38 | issue = 1 | pages = 178–86 |date=July 2003 | pmid = 12830000 | doi = 10.1053/jhep.2003.50270 }}</ref><ref name="pmid11960376">{{cite journal |vauthors=Oneyama C, Nakano H, Sharma SV | title = UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug | journal = Oncogene | volume = 21 | issue = 13 | pages = 2037–50 |date=March 2002 | pmid = 11960376 | doi = 10.1038/sj.onc.1205271 }}</ref><ref name="pmid8227214">{{cite journal |vauthors=Navarro P, Lozano E, Cano A | title = Expression of E- or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells. Possible involvement of plakoglobin | journal = J. Cell Sci. | volume = 105 | issue = 4| pages = 923–34 |date=August 1993 | pmid = 8227214 | doi = }}</ref><ref name="pmid9233779">{{cite journal |vauthors=Takahashi K, Suzuki K, Tsukatani Y | title = Induction of tyrosine phosphorylation and association of beta-catenin with EGF receptor upon tryptic digestion of quiescent cells at confluence | journal = Oncogene | volume = 15 | issue = 1 | pages = 71–8 |date=July 1997 | pmid = 9233779 | doi = 10.1038/sj.onc.1201160 }}</ref><ref name="pmid10772923">{{cite journal |vauthors=Dobrosotskaya IY, James GL | title = MAGI-1 interacts with beta-catenin and is associated with cell-cell adhesion structures | journal = Biochem. Biophys. Res. Commun. | volume = 270 | issue = 3 | pages = 903–9 |date=April 2000 | pmid = 10772923 | doi = 10.1006/bbrc.2000.2471 }}</ref><ref name="pmid11113628">{{cite journal |vauthors=Geng L, Burrow CR, Li HP, Wilson PD | title = Modification of the composition of polycystin-1 multiprotein complexes by calcium and tyrosine phosphorylation | journal = Biochim. Biophys. Acta | volume = 1535 | issue = 1 | pages = 21–35 |date=December 2000 | pmid = 11113628 | doi = 10.1016/S0925-4439(00)00079-X}}</ref><ref name="pmid12169098">{{cite journal |vauthors=Rao RK, Basuroy S, Rao VU, Karnaky Jr KJ, Gupta A | title = Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress | journal = Biochem. J. | volume = 368 | issue = Pt 2 | pages = 471–81 |date=December 2002 | pmid = 12169098 | pmc = 1222996 | doi = 10.1042/BJ20011804 }}</ref><ref name="pmid11348595">{{cite journal |vauthors=Huber AH, Weis WI | title = The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin | journal = Cell | volume = 105 | issue = 3 | pages = 391–402 |date=May 2001 | pmid = 11348595 | doi = 10.1016/S0092-8674(01)00330-0 }}</ref><ref name="pmid10381631">{{cite journal |vauthors=Schmeiser K, Grand RJ | title = The fate of E- and P-cadherin during the early stages of apoptosis | journal = Cell Death Differ. | volume = 6 | issue = 4 | pages = 377–86 |date=April 1999 | pmid = 10381631 | doi = 10.1038/sj.cdd.4400504 }}</ref><ref name="pmid18593907">{{cite journal |vauthors=Pai R, Dunlap D, Qing J, Mohtashemi I, Hotzel K, French DM | title = Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling | journal = Cancer Res. | volume = 68 | issue = 13 | pages = 5086–95 |date=July 2008 | pmid = 18593907 | doi = 10.1158/0008-5472.CAN-07-2325 }}</ref>
* [[Beta-catenin|CTNNB1]],<ref name="pmid12634428">{{cite journal | vauthors = Kang JS, Feinleib JL, Knox S, Ketteringham MA, Krauss RS | title = Promyogenic members of the Ig and cadherin families associate to positively regulate differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 7 | pages = 3989–94 | date = April 2003 | pmid = 12634428 | pmc = 153035 | doi = 10.1073/pnas.0736565100 }}</ref><ref name="pmid11254878">{{cite journal | vauthors = Davies G, Jiang WG, Mason MD | title = HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells | journal = International Journal of Molecular Medicine | volume = 7 | issue = 4 | pages = 385–8 | date = April 2001 | pmid = 11254878 | doi = 10.3892/ijmm.7.4.385 }}</ref><ref name="pmid7542250">{{cite journal | vauthors = Kinch MS, Clark GJ, Der CJ, Burridge K | title = Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia | journal = The Journal of Cell Biology | volume = 130 | issue = 2 | pages = 461–71 | date = July 1995 | pmid = 7542250 | pmc = 2199929 | doi = 10.1083/jcb.130.2.461 }}</ref><ref name="pmid9535896">{{cite journal | vauthors = Hazan RB, Norton L | title = The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton | journal = The Journal of Biological Chemistry | volume = 273 | issue = 15 | pages = 9078–84 | date = April 1998 | pmid = 9535896 | doi = 10.1074/jbc.273.15.9078 }}</ref><ref name="pmid12640114">{{cite journal | vauthors = Piedra J, Miravet S, Castaño J, Pálmer HG, Heisterkamp N, García de Herreros A, Duñach M | title = p120 Catenin-associated Fer and Fyn tyrosine kinases regulate beta-catenin Tyr-142 phosphorylation and beta-catenin-alpha-catenin Interaction | journal = Molecular and Cellular Biology | volume = 23 | issue = 7 | pages = 2287–97 | date = April 2003 | pmid = 12640114 | pmc = 150740 | doi = 10.1128/MCB.23.7.2287-2297.2003 }}</ref><ref name="pmid7876318">{{cite journal | vauthors = Shibamoto S, Hayakawa M, Takeuchi K, Hori T, Miyazawa K, Kitamura N, Johnson KR, Wheelock MJ, Matsuyoshi N, Takeichi M | title = Association of p120, a tyrosine kinase substrate, with E-cadherin/catenin complexes | journal = The Journal of Cell Biology | volume = 128 | issue = 5 | pages = 949–57 | date = March 1995 | pmid = 7876318 | pmc = 2120395 | doi = 10.1083/jcb.128.5.949 }}</ref><ref name="pmid11712088">{{cite journal | vauthors = Kucerová D, Sloncová E, Tuhácková Z, Vojtechová M, Sovová V | title = Expression and interaction of different catenins in colorectal carcinoma cells | journal = International Journal of Molecular Medicine | volume = 8 | issue = 6 | pages = 695–8 | date = December 2001 | pmid = 11712088 | doi = 10.3892/ijmm.8.6.695 }}</ref><ref name="pmid7954478">{{cite journal | vauthors = Oyama T, Kanai Y, Ochiai A, Akimoto S, Oda T, Yanagihara K, Nagafuchi A, Tsukita S, Shibamoto S, Ito F | title = A truncated beta-catenin disrupts the interaction between E-cadherin and alpha-catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines | journal = Cancer Research | volume = 54 | issue = 23 | pages = 6282–7 | date = December 1994 | pmid = 7954478 | doi = }}</ref><ref name="pmid9405455">{{cite journal | vauthors = Hazan RB, Kang L, Roe S, Borgen PI, Rimm DL | title = Vinculin is associated with the E-cadherin adhesion complex | journal = The Journal of Biological Chemistry | volume = 272 | issue = 51 | pages = 32448–53 | date = December 1997 | pmid = 9405455 | doi = 10.1074/jbc.272.51.32448 }}</ref><ref name="pmid12061792">{{cite journal | vauthors = Jiang MC, Liao CF, Tai CC | title = CAS/CSE 1 stimulates E-cadhrin-dependent cell polarity in HT-29 human colon epithelial cells | journal = Biochemical and Biophysical Research Communications | volume = 294 | issue = 4 | pages = 900–5 | date = June 2002 | pmid = 12061792 | doi = 10.1016/S0006-291X(02)00551-X }}</ref><ref name="pmid11245482">{{cite journal | vauthors = Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A, Dunach M, Neckers LM | title = Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription | journal = Cancer Research | volume = 61 | issue = 4 | pages = 1671–7 | date = February 2001 | pmid = 11245482 | doi = }}</ref><ref name="pmid9819408">{{cite journal | vauthors = Li Y, Bharti A, Chen D, Gong J, Kufe D | title = Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin | journal = Molecular and Cellular Biology | volume = 18 | issue = 12 | pages = 7216–24 | date = December 1998 | pmid = 9819408 | pmc = 109303 | doi = 10.1128/mcb.18.12.7216 }}</ref><ref name="pmid15023525">{{cite journal | vauthors = Wendeler MW, Praus M, Jung R, Hecking M, Metzig C, Gessner R | title = Ksp-cadherin is a functional cell-cell adhesion molecule related to LI-cadherin | journal = Experimental Cell Research | volume = 294 | issue = 2 | pages = 345–55 | date = April 2004 | pmid = 15023525 | doi = 10.1016/j.yexcr.2003.11.022 }}</ref><ref name="pmid12830000">{{cite journal | vauthors = Shibata T, Chuma M, Kokubu A, Sakamoto M, Hirohashi S | title = EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma | journal = Hepatology | volume = 38 | issue = 1 | pages = 178–86 | date = July 2003 | pmid = 12830000 | doi = 10.1053/jhep.2003.50270 }}</ref><ref name="pmid11960376">{{cite journal | vauthors = Oneyama C, Nakano H, Sharma SV | title = UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug | journal = Oncogene | volume = 21 | issue = 13 | pages = 2037–50 | date = March 2002 | pmid = 11960376 | doi = 10.1038/sj.onc.1205271 }}</ref><ref name="pmid8227214">{{cite journal | vauthors = Navarro P, Lozano E, Cano A | title = Expression of E- or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells. Possible involvement of plakoglobin | journal = Journal of Cell Science | volume = 105 ( Pt 4) | issue = 4 | pages = 923–34 | date = August 1993 | pmid = 8227214 | doi = }}</ref><ref name="pmid9233779">{{cite journal | vauthors = Takahashi K, Suzuki K, Tsukatani Y | title = Induction of tyrosine phosphorylation and association of beta-catenin with EGF receptor upon tryptic digestion of quiescent cells at confluence | journal = Oncogene | volume = 15 | issue = 1 | pages = 71–8 | date = July 1997 | pmid = 9233779 | doi = 10.1038/sj.onc.1201160 }}</ref><ref name="pmid10772923">{{cite journal | vauthors = Dobrosotskaya IY, James GL | title = MAGI-1 interacts with beta-catenin and is associated with cell-cell adhesion structures | journal = Biochemical and Biophysical Research Communications | volume = 270 | issue = 3 | pages = 903–9 | date = April 2000 | pmid = 10772923 | doi = 10.1006/bbrc.2000.2471 }}</ref><ref name="pmid11113628">{{cite journal | vauthors = Geng L, Burrow CR, Li HP, Wilson PD | title = Modification of the composition of polycystin-1 multiprotein complexes by calcium and tyrosine phosphorylation | journal = Biochimica et Biophysica Acta | volume = 1535 | issue = 1 | pages = 21–35 | date = December 2000 | pmid = 11113628 | doi = 10.1016/S0925-4439(00)00079-X }}</ref><ref name="pmid12169098">{{cite journal | vauthors = Rao RK, Basuroy S, Rao VU, Karnaky KJ, Gupta A | title = Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress | journal = The Biochemical Journal | volume = 368 | issue = Pt 2 | pages = 471–81 | date = December 2002 | pmid = 12169098 | pmc = 1222996 | doi = 10.1042/BJ20011804 }}</ref><ref name="pmid11348595">{{cite journal | vauthors = Huber AH, Weis WI | title = The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin | journal = Cell | volume = 105 | issue = 3 | pages = 391–402 | date = May 2001 | pmid = 11348595 | doi = 10.1016/S0092-8674(01)00330-0 }}</ref><ref name="pmid10381631">{{cite journal | vauthors = Schmeiser K, Grand RJ | title = The fate of E- and P-cadherin during the early stages of apoptosis | journal = Cell Death and Differentiation | volume = 6 | issue = 4 | pages = 377–86 | date = April 1999 | pmid = 10381631 | doi = 10.1038/sj.cdd.4400504 }}</ref><ref name="pmid18593907">{{cite journal | vauthors = Pai R, Dunlap D, Qing J, Mohtashemi I, Hotzel K, French DM | title = Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling | journal = Cancer Research | volume = 68 | issue = 13 | pages = 5086–95 | date = July 2008 | pmid = 18593907 | doi = 10.1158/0008-5472.CAN-07-2325 }}</ref>
* [[Catenin (cadherin-associated protein), alpha 1|CTNNA1]]<ref name=pmid7542250/><ref name=pmid11960376/><ref name=pmid8227214/><ref name=pmid9233779/><ref name=pmid10381631/>
* [[Catenin (cadherin-associated protein), alpha 1|CTNNA1]]<ref name=pmid7542250/><ref name=pmid11960376/><ref name=pmid8227214/><ref name=pmid9233779/><ref name=pmid10381631/>
*  [[FOXM1]],<ref name="pmid18758239">{{cite journal |vauthors=Laoukili J, Alvarez-Fernandez M, Stahl M, Medema RH | title = FoxM1 is degraded at mitotic exit in a Cdh1-dependent manner | journal = Cell Cycle | volume = 7 | issue = 17 | pages = 2720–6 |date=September 2008 | pmid = 18758239 | doi = 10.4161/cc.7.17.6580 }}</ref>
*  [[FOXM1]],<ref name="pmid18758239">{{cite journal | vauthors = Laoukili J, Alvarez-Fernandez M, Stahl M, Medema RH | title = FoxM1 is degraded at mitotic exit in a Cdh1-dependent manner | journal = Cell Cycle | volume = 7 | issue = 17 | pages = 2720–6 | date = September 2008 | pmid = 18758239 | doi = 10.4161/cc.7.17.6580 }}</ref>
* [[HDAC1]],<ref name="pmid15388328">{{cite journal |vauthors=Yoon YM, Baek KH, Jeong SJ, Shin HJ, Ha GH, Jeon AH, Hwang SG, Chun JS, Lee CW | title = WD repeat-containing mitotic checkpoint proteins act as transcriptional repressors during interphase | journal = FEBS Lett. | volume = 575 | issue = 1–3 | pages = 23–9 |date=September 2004 | pmid = 15388328 | doi = 10.1016/j.febslet.2004.07.089 }}</ref>
* [[HDAC1]],<ref name="pmid15388328">{{cite journal | vauthors = Yoon YM, Baek KH, Jeong SJ, Shin HJ, Ha GH, Jeon AH, Hwang SG, Chun JS, Lee CW | title = WD repeat-containing mitotic checkpoint proteins act as transcriptional repressors during interphase | journal = FEBS Letters | volume = 575 | issue = 1-3 | pages = 23–9 | date = September 2004 | pmid = 15388328 | doi = 10.1016/j.febslet.2004.07.089 }}</ref>
* [[Histone deacetylase 2|HDAC2]],<ref name=pmid15388328/>
* [[Histone deacetylase 2|HDAC2]],<ref name=pmid15388328/>
* [[IQGAP1]],<ref name="pmid10608854">{{cite journal |vauthors=Li Z, Kim SH, Higgins JM, Brenner MB, Sacks DB | title = IQGAP1 and calmodulin modulate E-cadherin function | journal = J. Biol. Chem. | volume = 274 | issue = 53 | pages = 37885–92 |date=December 1999 | pmid = 10608854 | doi = 10.1074/jbc.274.53.37885}}</ref>
* [[IQGAP1]],<ref name="pmid10608854">{{cite journal | vauthors = Li Z, Kim SH, Higgins JM, Brenner MB, Sacks DB | title = IQGAP1 and calmodulin modulate E-cadherin function | journal = The Journal of Biological Chemistry | volume = 274 | issue = 53 | pages = 37885–92 | date = December 1999 | pmid = 10608854 | doi = 10.1074/jbc.274.53.37885 }}</ref>
*  [[FYN]],<ref name=pmid12640114/>
*  [[FYN]],<ref name=pmid12640114/>
* [[NEDD9]],<ref name="pmid15144564">{{cite journal |vauthors=Nourry C, Maksumova L, Pang M, Liu X, Wang T | title = Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1 | journal = BMC Cell Biol. | volume = 5 | issue = 1| pages = 20 |date=May 2004 | pmid = 15144564 | pmc = 420458 | doi = 10.1186/1471-2121-5-20 }}</ref>
* [[NEDD9]],<ref name="pmid15144564">{{cite journal | vauthors = Nourry C, Maksumova L, Pang M, Liu X, Wang T | title = Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1 | journal = BMC Cell Biology | volume = 5 | issue = 1 | pages = 20 | date = May 2004 | pmid = 15144564 | pmc = 420458 | doi = 10.1186/1471-2121-5-20 }}</ref>
* [[Plakoglobin]],<ref name=pmid7542250/><ref name=pmid9535896/><ref name="pmid8074697">{{cite journal |vauthors=Shibata T, Gotoh M, Ochiai A, Hirohashi S | title = Association of plakoglobin with APC, a tumor suppressor gene product, and its regulation by tyrosine phosphorylation | journal = Biochem. Biophys. Res. Commun. | volume = 203 | issue = 1 | pages = 519–22 |date=August 1994 | pmid = 8074697 | doi = 10.1006/bbrc.1994.2213 }}</ref><ref name="pmid8207061">{{cite journal |vauthors=Hinck L, Näthke IS, Papkoff J, Nelson WJ | title = Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly | journal = J. Cell Biol. | volume = 125 | issue = 6 | pages = 1327–40 |date=June 1994 | pmid = 8207061 | pmc = 2290923 | doi = 10.1083/jcb.125.6.1327 }}</ref><ref name="pmid1639850">{{cite journal |vauthors=Knudsen KA, Wheelock MJ | title = Plakoglobin, or an 83-kD homologue distinct from beta-catenin, interacts with E-cadherin and N-cadherin | journal = J. Cell Biol. | volume = 118 | issue = 3 | pages = 671–9 |date=August 1992 | pmid = 1639850 | pmc = 2289540 | doi = 10.1083/jcb.118.3.671 }}</ref>
* [[Plakoglobin]],<ref name=pmid7542250/><ref name=pmid9535896/><ref name="pmid8074697">{{cite journal | vauthors = Shibata T, Gotoh M, Ochiai A, Hirohashi S | title = Association of plakoglobin with APC, a tumor suppressor gene product, and its regulation by tyrosine phosphorylation | journal = Biochemical and Biophysical Research Communications | volume = 203 | issue = 1 | pages = 519–22 | date = August 1994 | pmid = 8074697 | doi = 10.1006/bbrc.1994.2213 }}</ref><ref name="pmid8207061">{{cite journal | vauthors = Hinck L, Näthke IS, Papkoff J, Nelson WJ | title = Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly | journal = The Journal of Cell Biology | volume = 125 | issue = 6 | pages = 1327–40 | date = June 1994 | pmid = 8207061 | pmc = 2290923 | doi = 10.1083/jcb.125.6.1327 }}</ref><ref name="pmid1639850">{{cite journal | vauthors = Knudsen KA, Wheelock MJ | title = Plakoglobin, or an 83-kD homologue distinct from beta-catenin, interacts with E-cadherin and N-cadherin | journal = The Journal of Cell Biology | volume = 118 | issue = 3 | pages = 671–9 | date = August 1992 | pmid = 1639850 | pmc = 2289540 | doi = 10.1083/jcb.118.3.671 }}</ref>
*  [[Vinculin]],<ref name=pmid9535896/><ref name=pmid9405455/>
*  [[Vinculin]],<ref name=pmid9535896/><ref name=pmid9405455/>
{{Div col end}}
{{Div col end}}
*  PTPmu([[PTPRM]])<ref name="pmid7642713">{{cite journal|vauthors=Brady-Kalnay SM, Rimm DL, Tonks NK | title=Receptor protein tyrosine phosphatase PTPmu associates with cadherins and catenins in vivo. | journal=J Cell Biol | year= 1995 | volume= 130 | issue= 4 | pages= 977–86 | pmid=7642713 | doi= 10.1083/jcb.130.4.977| pmc=2199947 | url= }}</ref><ref name="pmid9531566">{{cite journal|vauthors=Brady-Kalnay SM, Mourton T, Nixon JP, Pietz GE, Kinch M, Chen H | title=Dynamic interaction of PTPmu with multiple cadherins in vivo. | journal=J Cell Biol | year= 1998 | volume= 141 | issue= 1 | pages= 287–96 | pmid=9531566 | doi= 10.1083/jcb.141.1.287| pmc=2132733 | url= |display-authors=etal}}</ref>
*  PTPmu([[PTPRM]])<ref name="pmid7642713">{{cite journal | vauthors = Brady-Kalnay SM, Rimm DL, Tonks NK | title = Receptor protein tyrosine phosphatase PTPmu associates with cadherins and catenins in vivo | journal = The Journal of Cell Biology | volume = 130 | issue = 4 | pages = 977–86 | date = August 1995 | pmid = 7642713 | pmc = 2199947 | doi = 10.1083/jcb.130.4.977 }}</ref><ref name="pmid9531566">{{cite journal | vauthors = Brady-Kalnay SM, Mourton T, Nixon JP, Pietz GE, Kinch M, Chen H, Brackenbury R, Rimm DL, Del Vecchio RL, Tonks NK | title = Dynamic interaction of PTPmu with multiple cadherins in vivo | journal = The Journal of Cell Biology | volume = 141 | issue = 1 | pages = 287–96 | date = April 1998 | pmid = 9531566 | pmc = 2132733 | doi = 10.1083/jcb.141.1.287 }}</ref>
*  PTPrho([[PTPRT]])<ref name="pmid16973135">{{cite journal|vauthors=Besco JA, Hooft van Huijsduijnen R, Frostholm A, Rotter A | title=Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT). | journal=Brain Res | year= 2006 | volume= 1116 | issue= 1 | pages= 50–7 | pmid=16973135 | doi=10.1016/j.brainres.2006.07.122 | pmc= | url=https://www.ncbi.nlm.nih.gov/pubmed/16973135  }}</ref>
*  PTPrho([[PTPRT]])<ref name="pmid16973135">{{cite journal | vauthors = Besco JA, Hooft van Huijsduijnen R, Frostholm A, Rotter A | title = Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT) | journal = Brain Research | volume = 1116 | issue = 1 | pages = 50–7 | date = October 2006 | pmid = 16973135 | pmc =  | doi = 10.1016/j.brainres.2006.07.122 }}</ref>


==Cadherin-1 and cancer==
==Cadherin-1 and cancer==


=== Cadherin-1 in metastasis===
=== Cadherin-1 in metastasis===
Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT ([[epithelial-mesenchymal transition]]) and MET ([[mesenchymal-epithelial transition]]). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma.<ref name="PMID-19262571">{{cite journal | author=Weinberg, Robert A.| title=Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits | journal=Nat Rev Cancer | volume=9 | issue=4 | pages=265–273 |date=April 2009 | pmid=19262571 | doi=10.1038/nrc2620}}</ref>
Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT ([[epithelial-mesenchymal transition]]) and MET ([[mesenchymal-epithelial transition]]). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma.<ref name="PMID-19262571">{{cite journal | vauthors = Polyak K, Weinberg RA | title = Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits | journal = Nature Reviews. Cancer | volume = 9 | issue = 4 | pages = 265–73 | date = April 2009 | pmid = 19262571 | doi = 10.1038/nrc2620 }}</ref>


1. E-cadherin in EMT:
1. E-cadherin in EMT:
Line 63: Line 54:
===Cancer examples===
===Cancer examples===


*Inactivation of CDH1 (accompany with loss of the wild-type allele) in 56% of lobular breast carcinomas.<ref name="PMC394735">{{cite journal | author=G Berx| title=E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis | journal=EMBO J. | volume=14 | issue=24 | pages=6107–6115 |date=December 1995 | pmc=394735 | pmid=8557030|display-authors=etal}}</ref><ref name="PMID=8934538">{{cite journal | author=G Berx| title=E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. | journal=Oncogene | volume=13 | issue=9 | pages=1919–1925 |date=November 1996 | pmid=8934538|display-authors=etal}}</ref>
*Inactivation of CDH1 (accompany with loss of the wild-type allele) in 56% of lobular breast carcinomas.<ref name="PMC394735">{{cite journal | vauthors = Berx G, Cleton-Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C, van Roy F | title = E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers | journal = The EMBO Journal | volume = 14 | issue = 24 | pages = 6107–15 | date = December 1995 | pmid = 8557030 | pmc = 394735 }}</ref><ref name="PMID=8934538">{{cite journal | vauthors = Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C | title = E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain | journal = Oncogene | volume = 13 | issue = 9 | pages = 1919–25 | date = November 1996 | pmid = 8934538 }}</ref>
*Inactivation of CDH1 in 50% of diffuse gastric carcinomas.<ref name="PMID=8033105">{{cite journal | author=Becker KF| title=E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. | journal=Cancer Res | volume=54 | issue=14 | pages=3845–3852 |date=November 1994 | pmid=8033105|display-authors=etal}}</ref>
*Inactivation of CDH1 in 50% of diffuse gastric carcinomas.<ref name="PMID=8033105">{{cite journal | vauthors = Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, Höfler H | title = E-cadherin gene mutations provide clues to diffuse type gastric carcinomas | journal = Cancer Research | volume = 54 | issue = 14 | pages = 3845–52 | date = July 1994 | pmid = 8033105 }}</ref>
*Complete loss of E-cadherin protein expression in 84% of lobular breast carcinomas.<ref name="PMID=9496256">{{cite journal | author=De Leeuw WJ| title=Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. | journal=J Pathol. | volume=183 | issue=4 | pages=404–411 |date=December 1997 | pmid=9496256 | doi=10.1002/(SICI)1096-9896(199712)183:4<404::AID-PATH1148>3.0.CO;2-9|display-authors=etal}}</ref>
*Complete loss of E-cadherin protein expression in 84% of lobular breast carcinomas.<ref name="PMID=9496256">{{cite journal | vauthors = De Leeuw WJ, Berx G, Vos CB, Peterse JL, Van de Vijver MJ, Litvinov S, Van Roy F, Cornelisse CJ, Cleton-Jansen AM | title = Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ | journal = The Journal of Pathology | volume = 183 | issue = 4 | pages = 404–11 | date = December 1997 | pmid = 9496256 | doi = 10.1002/(SICI)1096-9896(199712)183:4<404::AID-PATH1148>3.0.CO;2-9 }}</ref>


===Genetic and epigenetic control of CDH1===
===Genetic and epigenetic control of CDH1===


Several proteins such as SNAI1/SNAIL,<ref name="PMID=10655587">{{cite journal | author=De Leeuw WJ| title=The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. | journal=Nat Cell Biol | volume=2 | issue=2 | pages=84–89 |date=February 2000 | pmid=10655587 | doi=10.1038/35000034|display-authors=etal}}</ref><ref name="PMID=10655586">{{cite journal | author=Cano A| title=The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. | journal=Nat Cell Biol | volume=2 | issue=2 | pages=76–83 |date=February 2000 | pmid=10655586 | doi=10.1038/35000025|display-authors=etal}}</ref> ZFHX1B/SIP1,<ref name="PMID=11430829">{{cite journal | author=Comijn J| title=The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. | journal=Mol Cell | volume=7 | issue=6 | pages=1267–1278 |date=June 2001 | pmid=11430829 | doi=10.1016/S1097-2765(01)00260-X|display-authors=etal}}</ref> SNAI2/SLUG,<ref name="PMID=11912130">{{cite journal | author=Hajra KM| title=The SLUG zinc-finger protein represses E-cadherin in breast cancer. | journal=Cancer Res | volume=62 | issue=6 | pages=1613–1618 |date=March 2002 | pmid=11912130|display-authors=etal}}</ref><ref name="PMID=16024625">{{cite journal | author=De Craene B| title=The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. | journal=Cancer Res. | volume=65 | issue=14 | pages=6237–6244 |date=July 2005 | pmid=16024625 | doi=10.1158/0008-5472.CAN-04-3545|display-authors=etal}}</ref> TWIST1<ref name="PMID=15210113">{{cite journal | author=Yang J| title=Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. | journal=Cell | volume=117 | issue=7 | pages=927–939 |date=June 2004 | pmid=15210113 | doi=10.1016/j.cell.2004.06.006|display-authors=etal}}</ref> and DeltaEF1<ref name="PMID=15674322">{{cite journal | author=Eger A| title=DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. | journal=Oncogene | volume=24 | issue=14 | pages=2375–85 |date=Mar 2005 | pmid=15674322 | doi=10.1038/sj.onc.1208429|display-authors=etal}}</ref> have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells.<ref name="PMID=10655587"></ref><ref name="PMID=10655586"></ref><ref name="PMID=11430829"></ref><ref name="PMID=11912130"></ref><ref name="PMID=15210113"></ref><ref name="PMID=15674322"></ref> Another group of genes, such as AML1, p300 and HNF3,<ref name="PMID=16116478">{{cite journal | author=Liu YN| title=Regulatory mechanisms controlling human E-cadherin gene expression. | journal=Oncogene | volume=24 | issue=56 | pages=8277–90 |date=Dec 2005 | pmid=16116478 | doi=10.1038/sj.onc.1208991|display-authors=etal}}</ref> can upregulate the expression of E-cadherin.<ref name="PMID=16495925">{{cite journal | author=Lombaerts M| title=E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. | journal=Br J Cancer | volume=94 | issue=5 | pages=661–71 |date=Mar 2006 | pmid=16495925 | doi=10.1038/sj.bjc.6602996|display-authors=etal | pmc=2361216}}</ref>
Several proteins such as SNAI1/SNAIL,<ref name="PMID=10655587">{{cite journal | vauthors = Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, García De Herreros A | title = The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells | journal = Nature Cell Biology | volume = 2 | issue = 2 | pages = 84–9 | date = February 2000 | pmid = 10655587 | doi = 10.1038/35000034 }}</ref><ref name="PMID=10655586">{{cite journal | vauthors = Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA | title = The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression | journal = Nature Cell Biology | volume = 2 | issue = 2 | pages = 76–83 | date = February 2000 | pmid = 10655586 | doi = 10.1038/35000025 }}</ref> ZFHX1B/SIP1,<ref name="PMID=11430829">{{cite journal | vauthors = Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F | title = The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion | journal = Molecular Cell | volume = 7 | issue = 6 | pages = 1267–78 | date = June 2001 | pmid = 11430829 | doi = 10.1016/S1097-2765(01)00260-X }}</ref> SNAI2/SLUG,<ref name="PMID=11912130">{{cite journal | vauthors = Hajra KM, Chen DY, Fearon ER | title = The SLUG zinc-finger protein represses E-cadherin in breast cancer | journal = Cancer Research | volume = 62 | issue = 6 | pages = 1613–8 | date = March 2002 | pmid = 11912130 }}</ref><ref name="PMID=16024625">{{cite journal | vauthors = De Craene B, Gilbert B, Stove C, Bruyneel E, van Roy F, Berx G | title = The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program | journal = Cancer Research | volume = 65 | issue = 14 | pages = 6237–44 | date = July 2005 | pmid = 16024625 | doi = 10.1158/0008-5472.CAN-04-3545 }}</ref> TWIST1<ref name="PMID=15210113">{{cite journal | vauthors = Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA | title = Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis | journal = Cell | volume = 117 | issue = 7 | pages = 927–39 | date = June 2004 | pmid = 15210113 | doi = 10.1016/j.cell.2004.06.006 }}</ref> and DeltaEF1<ref name="PMID=15674322">{{cite journal | vauthors = Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, Berx G, Cano A, Beug H, Foisner R | title = DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells | journal = Oncogene | volume = 24 | issue = 14 | pages = 2375–85 | date = March 2005 | pmid = 15674322 | doi = 10.1038/sj.onc.1208429 }}</ref> have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells.<ref name="PMID=10655587"></ref><ref name="PMID=10655586"></ref><ref name="PMID=11430829"></ref><ref name="PMID=11912130"></ref><ref name="PMID=15210113"></ref><ref name="PMID=15674322"></ref> Another group of genes, such as AML1, p300 and HNF3,<ref name="PMID=16116478">{{cite journal | vauthors = Liu YN, Lee WW, Wang CY, Chao TH, Chen Y, Chen JH | title = Regulatory mechanisms controlling human E-cadherin gene expression | journal = Oncogene | volume = 24 | issue = 56 | pages = 8277–90 | date = December 2005 | pmid = 16116478 | doi = 10.1038/sj.onc.1208991 }}</ref> can upregulate the expression of E-cadherin.<ref name="PMID=16495925">{{cite journal | vauthors = Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, van Eijk R, Eilers PH, van de Water B, Cornelisse CJ, Cleton-Jansen AM | title = E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines | journal = British Journal of Cancer | volume = 94 | issue = 5 | pages = 661–71 | date = March 2006 | pmid = 16495925 | pmc = 2361216 | doi = 10.1038/sj.bjc.6602996 }}</ref>


In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with hypermethylation of CDH1 promoter, but in breast cancer cell lines with a CDH1 mutational inactivation EMT cannot happen. It contradicts the hypothesis that E-cadherin loss is the initial or primary cause for EMT. In conclusion, the results suggest that “E-cadherin transcriptional inactivation is an epi-phenomenon and part of an entire program, with much more severe effects than loss of E-cadherin expression alone”.<ref name="PMID=16495925">{{cite journal | author=Lombaerts M| title=E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. | journal=Br J Cancer | volume=94 | issue=5 | pages=661–71 |date=Mar 2006 | pmid=16495925 | doi=10.1038/sj.bjc.6602996|display-authors=etal | pmc=2361216}}</ref>
In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with hypermethylation of CDH1 promoter, but in breast cancer cell lines with a CDH1 mutational inactivation EMT cannot happen. It contradicts the hypothesis that E-cadherin loss is the initial or primary cause for EMT. In conclusion, the results suggest that “E-cadherin transcriptional inactivation is an epi-phenomenon and part of an entire program, with much more severe effects than loss of E-cadherin expression alone”.<ref name="PMID=16495925">{{cite journal | vauthors = Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, van Eijk R, Eilers PH, van de Water B, Cornelisse CJ, Cleton-Jansen AM | title = E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines | journal = British Journal of Cancer | volume = 94 | issue = 5 | pages = 661–71 | date = March 2006 | pmid = 16495925 | pmc = 2361216 | doi = 10.1038/sj.bjc.6602996 }}</ref>


Other studies also show that epigenetic regulation of E-cadherin expression occurs during metastasis. The methylation patterns of the E-cadherin 5’ CpG island are not stable. During metastatic progression of many cases of epithelial tumors, a transient loss of E-cadherin is seen and the heterogeneous loss of E-cadherin expression results from a heterogeneous pattern of promoter region methylation of E-cadherin.<ref name="PMID=10644736">{{cite journal | author=Graff JR| title=Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. | journal=J Biol Chem| volume=275 | issue=4 | pages=2727–32 |date=Jan 2000 | pmid=10644736 | doi=10.1074/jbc.275.4.2727|display-authors=etal}}</ref>
Other studies also show that epigenetic regulation of E-cadherin expression occurs during metastasis. The methylation patterns of the E-cadherin 5’ CpG island are not stable. During metastatic progression of many cases of epithelial tumors, a transient loss of E-cadherin is seen and the heterogeneous loss of E-cadherin expression results from a heterogeneous pattern of promoter region methylation of E-cadherin.<ref name="PMID=10644736">{{cite journal | vauthors = Graff JR, Gabrielson E, Fujii H, Baylin SB, Herman JG|authorlink3=Stephen B. Baylin|authorlink5=James G. Herman | title = Methylation patterns of the E-cadherin 5' CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression | journal = The Journal of Biological Chemistry | volume = 275 | issue = 4 | pages = 2727–32 | date = January 2000 | pmid = 10644736 | doi = 10.1074/jbc.275.4.2727 }}</ref>


==See also==
== See also ==
* [[Cluster of differentiation]]
* [[Cluster of differentiation]]


==References==
== References ==
{{reflist|colwidth=30em}}
{{reflist|colwidth=30em}}


==Further reading==
== Further reading ==
{{refbegin | colwidth = 30em}}
{{refbegin | colwidth = 30em}}
*{{cite journal |vauthors=Berx G, Becker KF, Höfler H, van Roy F |title=Mutations of the human E-cadherin (CDH1) gene. |journal=Hum. Mutat. |volume=12 |issue= 4 |pages= 226–37 |year= 1998 |pmid= 9744472 |doi= 10.1002/(SICI)1098-1004(1998)12:4<226::AID-HUMU2>3.0.CO;2-D }}
* {{cite journal | vauthors = Berx G, Becker KF, Höfler H, van Roy F | title = Mutations of the human E-cadherin (CDH1) gene | journal = Human Mutation | volume = 12 | issue = 4 | pages = 226–37 | year = 1998 | pmid = 9744472 | doi = 10.1002/(SICI)1098-1004(1998)12:4<226::AID-HUMU2>3.0.CO;2-D }}
*{{cite journal |vauthors=Wijnhoven BP, Dinjens WN, Pignatelli M |title=E-cadherin-catenin cell-cell adhesion complex and human cancer. |journal=The British journal of surgery |volume=87 |issue= 8 |pages= 992–1005 |year= 2000 |pmid= 10931041 |doi= 10.1046/j.1365-2168.2000.01513.x }}
* {{cite journal | vauthors = Wijnhoven BP, Dinjens WN, Pignatelli M | title = E-cadherin-catenin cell-cell adhesion complex and human cancer | journal = The British Journal of Surgery | volume = 87 | issue = 8 | pages = 992–1005 | date = August 2000 | pmid = 10931041 | doi = 10.1046/j.1365-2168.2000.01513.x }}
*{{cite journal | author=Beavon IR |title=The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. |journal=Eur. J. Cancer |volume=36 |issue= 13 Spec No |pages= 1607–20 |year= 2000 |pmid= 10959047 |doi=10.1016/S0959-8049(00)00158-1 }}
* {{cite journal | vauthors = Beavon IR | title = The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation | journal = European Journal of Cancer | volume = 36 | issue = 13 Spec No | pages = 1607–20 | date = August 2000 | pmid = 10959047 | doi = 10.1016/S0959-8049(00)00158-1 }}
*{{cite journal | author=Wilson PD |title=Polycystin: new aspects of structure, function, and regulation. |journal=J. Am. Soc. Nephrol. |volume=12 |issue= 4 |pages= 834–45 |year= 2001 |pmid= 11274246 |doi=  }}
* {{cite journal | vauthors = Wilson PD | title = Polycystin: new aspects of structure, function, and regulation | journal = Journal of the American Society of Nephrology | volume = 12 | issue = 4 | pages = 834–45 | date = April 2001 | pmid = 11274246 | doi =  }}
*{{cite journal |vauthors=Chun YS, Lindor NM, Smyrk TC |title=Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? |journal=Cancer |volume=92 |issue= 1 |pages= 181–7 |year= 2001 |pmid= 11443625 |doi=10.1002/1097-0142(20010701)92:1<181::AID-CNCR1307>3.0.CO;2-J |display-authors=etal}}
* {{cite journal | vauthors = Chun YS, Lindor NM, Smyrk TC, Petersen BT, Burgart LJ, Guilford PJ, Donohue JH | title = Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? | journal = Cancer | volume = 92 | issue = 1 | pages = 181–7 | date = July 2001 | pmid = 11443625 | doi = 10.1002/1097-0142(20010701)92:1<181::AID-CNCR1307>3.0.CO;2-J }}
*{{cite journal |vauthors=Hazan RB, Qiao R, Keren R |title=Cadherin switch in tumor progression. |journal=Ann. N. Y. Acad. Sci. |volume=1014 |issue= 1|pages= 155–63 |year= 2004 |pmid= 15153430 |doi=10.1196/annals.1294.016 |display-authors=etal}}
* {{cite journal | vauthors = Hazan RB, Qiao R, Keren R, Badano I, Suyama K | title = Cadherin switch in tumor progression | journal = Annals of the New York Academy of Sciences | volume = 1014 | issue = 1 | pages = 155–63 | date = April 2004 | pmid = 15153430 | doi = 10.1196/annals.1294.016 }}
*{{cite journal |vauthors=Bryant DM, Stow JL |title=The ins and outs of E-cadherin trafficking. |journal=Trends Cell Biol. |volume=14 |issue= 8 |pages= 427–34 |year= 2005 |pmid= 15308209 |doi= 10.1016/j.tcb.2004.07.007 }}
* {{cite journal | vauthors = Bryant DM, Stow JL | title = The ins and outs of E-cadherin trafficking | journal = Trends in Cell Biology | volume = 14 | issue = 8 | pages = 427–34 | date = August 2004 | pmid = 15308209 | doi = 10.1016/j.tcb.2004.07.007 }}
*{{cite journal |vauthors=Wang HD, Ren J, Zhang L |title=CDH1 germline mutation in hereditary gastric carcinoma. |journal=World J. Gastroenterol. |volume=10 |issue= 21 |pages= 3088–93 |year= 2004 |pmid= 15457549 |doi=  }}
* {{cite journal | vauthors = Wang HD, Ren J, Zhang L | title = CDH1 germline mutation in hereditary gastric carcinoma | journal = World Journal of Gastroenterology | volume = 10 | issue = 21 | pages = 3088–93 | date = November 2004 | pmid = 15457549 | doi =  }}
*{{cite journal |vauthors=Reynolds AB, Carnahan RH |title=Regulation of cadherin stability and turnover by p120ctn: implications in disease and cancer. |journal=Semin. Cell Dev. Biol. |volume=15 |issue= 6 |pages= 657–63 |year= 2005 |pmid= 15561585 |doi= 10.1016/j.semcdb.2004.09.003 }}
* {{cite journal | vauthors = Reynolds AB, Carnahan RH | title = Regulation of cadherin stability and turnover by p120ctn: implications in disease and cancer | journal = Seminars in Cell & Developmental Biology | volume = 15 | issue = 6 | pages = 657–63 | date = December 2004 | pmid = 15561585 | doi = 10.1016/j.semcdb.2004.09.003 }}
*{{cite journal |vauthors=Moran CJ, Joyce M, McAnena OJ |title=CDH1 associated gastric cancer: a report of a family and review of the literature. |journal=Eur J Surg Oncol |volume=31 |issue= 3 |pages= 259–64 |year= 2005 |pmid= 15780560 |doi= 10.1016/j.ejso.2004.12.010 }}
* {{cite journal | vauthors = Moran CJ, Joyce M, McAnena OJ | title = CDH1 associated gastric cancer: a report of a family and review of the literature | journal = European Journal of Surgical Oncology | volume = 31 | issue = 3 | pages = 259–64 | date = April 2005 | pmid = 15780560 | doi = 10.1016/j.ejso.2004.12.010 }}
*{{cite journal |vauthors=Georgolios A, Batistatou A, Manolopoulos L, Charalabopoulos K |title=Role and expression patterns of E-cadherin in head and neck squamous cell carcinoma (HNSCC). |journal=J. Exp. Clin. Cancer Res. |volume=25 |issue= 1 |pages= 5–14 |year= 2006 |pmid= 16761612 |doi=  }}
* {{cite journal | vauthors = Georgolios A, Batistatou A, Manolopoulos L, Charalabopoulos K | title = Role and expression patterns of E-cadherin in head and neck squamous cell carcinoma (HNSCC) | journal = Journal of Experimental & Clinical Cancer Research | volume = 25 | issue = 1 | pages = 5–14 | date = March 2006 | pmid = 16761612 | doi =  }}
*{{cite journal |vauthors=Renaud-Young M, Gallin WJ |title=In the first extracellular domain of E-cadherin, heterophilic interactions, but not the conserved His-Ala-Val motif, are required for adhesion |journal=Journal of Biological Chemistry |volume=277 |issue= 42 |pages= 39609–39616 |year= 2002 |pmid= 12154084 |doi=10.1074/jbc.M201256200 }}
* {{cite journal | vauthors = Renaud-Young M, Gallin WJ | title = In the first extracellular domain of E-cadherin, heterophilic interactions, but not the conserved His-Ala-Val motif, are required for adhesion | journal = The Journal of Biological Chemistry | volume = 277 | issue = 42 | pages = 39609–16 | date = October 2002 | pmid = 12154084 | doi = 10.1074/jbc.M201256200 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|CDH1+protein,+human}}
* {{MeshName|CDH1+protein,+human}}
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hgc  GeneReviews/NCBI/NIH/UW entry on Hereditary Diffuse Gastric Cancer]
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hgc  GeneReviews/NCBI/NIH/UW entry on Hereditary Diffuse Gastric Cancer]

Revision as of 15:47, 9 December 2018

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Cadherin-1 also known as CAM 120/80 or epithelial cadherin (E-cadherin) or uvomorulin is a protein that in humans is encoded by the CDH1 gene.[1] CDH1 has also been designated as CD324 (cluster of differentiation 324). It is a tumor suppressor gene.[2][3]

Function

Cadherin-1 is a classical member of the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells, and the cytoplasmic domain is required for internalization. Identified transcript variants arise from mutation at consensus splice sites.[4]

E-cadherin (epithelial) is the most well-studied member of the cadherin family. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds p120-catenin and beta-catenin. The intracellular domain contains a highly-phosphorylated region vital to beta-catenin binding and, therefore, to E-cadherin function.[citation needed] Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the cytoskeleton.

E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction.[citation needed] In adult tissues, E-cadherin is expressed in epithelial tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface.[citation needed] Cell-cell interactions mediated by E-cadherin are crucial to blastula formation in many animals.[5]

Clinical significance

Loss of E-cadherin function or expression has been implicated in cancer progression and metastasis.[6][7] E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the basement membrane and invade surrounding tissues.[7] E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive ductal carcinoma, E-cadherin expression is markedly reduced or absent in the great majority of invasive lobular carcinomas when studied by immunohistochemistry.[8]

Interactions

CDH1 (gene) has been shown to interact with

Cadherin-1 and cancer

Cadherin-1 in metastasis

Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma.[49]

1. E-cadherin in EMT:

E-cadherin is a crucial type of cell-cell adhesion to hold the epithelial cells tight together. E-cadherin can sequester β-catenin on the cell membrane by the cytoplasmic tail of E-cadherin. Loss of E-cadherin expression results in releasing β-catenin into the cytoplasm. Liberated β-catenin molecules may migrate into the nucleus and trigger the expression of EMT-inducing transcription factors. Together with other mechanisms, such as constitutive RTK activation, E-cadherin loss can lead cancer cells to the mesenchymal state and undergo metastasis. E-cadherin is an important switch in EMT.[49]

2. E-cadherin in MET:

The mesenchymal state cancer cells migrate to new sites and may undergo METs in certain favorable microenvironment. For example, the cancer cells can recognize differentiated epithelial cell features in the new sites and upregulate E-cadherin expression. Those cancer cells can form cell-cell adhesions again and return to an epithelial state.[49]

Cancer examples

  • Inactivation of CDH1 (accompany with loss of the wild-type allele) in 56% of lobular breast carcinomas.[50][51]
  • Inactivation of CDH1 in 50% of diffuse gastric carcinomas.[52]
  • Complete loss of E-cadherin protein expression in 84% of lobular breast carcinomas.[53]

Genetic and epigenetic control of CDH1

Several proteins such as SNAI1/SNAIL,[54][55] ZFHX1B/SIP1,[56] SNAI2/SLUG,[57][58] TWIST1[59] and DeltaEF1[60] have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells.[54][55][56][57][59][60] Another group of genes, such as AML1, p300 and HNF3,[61] can upregulate the expression of E-cadherin.[62]

In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with hypermethylation of CDH1 promoter, but in breast cancer cell lines with a CDH1 mutational inactivation EMT cannot happen. It contradicts the hypothesis that E-cadherin loss is the initial or primary cause for EMT. In conclusion, the results suggest that “E-cadherin transcriptional inactivation is an epi-phenomenon and part of an entire program, with much more severe effects than loss of E-cadherin expression alone”.[62]

Other studies also show that epigenetic regulation of E-cadherin expression occurs during metastasis. The methylation patterns of the E-cadherin 5’ CpG island are not stable. During metastatic progression of many cases of epithelial tumors, a transient loss of E-cadherin is seen and the heterogeneous loss of E-cadherin expression results from a heterogeneous pattern of promoter region methylation of E-cadherin.[63]

See also

References

  1. ↑ Huntsman DG, Caldas C (Mar 1999). "Assignment1 of the E-cadherin gene (CDH1) to chromosome 16q22.1 by radiation hybrid mapping". Cytogenetics and Cell Genetics. 83 (1–2): 82–3. doi:10.1159/000015134. PMID 9925936.
  2. ↑ Semb H, Christofori G (December 1998). "The tumor-suppressor function of E-cadherin". American Journal of Human Genetics. 63 (6): 1588–93. doi:10.1086/302173. PMC 1377629. PMID 9837810.
  3. ↑ Wong AS, Gumbiner BM (June 2003). "Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin". The Journal of Cell Biology. 161 (6): 1191–203. doi:10.1083/jcb.200212033. PMC 2173007. PMID 12810698.
  4. ↑ "Entrez Gene: CDH1 cadherin 1, type 1, E-cadherin (epithelial)".
  5. ↑ Fleming TP, Papenbrock T, Fesenko I, Hausen P, Sheth B (August 2000). "Assembly of tight junctions during early vertebrate development". Seminars in Cell & Developmental Biology. 11 (4): 291–9. doi:10.1006/scdb.2000.0179. PMID 10966863.
  6. ↑ Beavon IR (August 2000). "The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation". European Journal of Cancer. 36 (13 Spec No): 1607–20. doi:10.1016/S0959-8049(00)00158-1. PMID 10959047.
  7. ↑ 7.0 7.1 Weinberg, Robert (2006). The Biology of Cancer. Garland Science. pp. 864 pages. ISBN 9780815340782.
  8. ↑ Rosen, P. Rosen's Breast Pathology, 3rd ed, 2009, p. 704. Lippincott Williams & Wilkins.
  9. ↑ Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HE, Behrens J, Sommer T, Birchmeier W (March 2002). "Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex". Nature Cell Biology. 4 (3): 222–31. doi:10.1038/ncb758. PMID 11836526.
  10. ↑ Vodermaier HC, Gieffers C, Maurer-Stroh S, Eisenhaber F, Peters JM (September 2003). "TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1". Current Biology. 13 (17): 1459–68. doi:10.1016/S0960-9822(03)00581-5. PMID 12956947.
  11. ↑ 11.0 11.1 Kang JS, Feinleib JL, Knox S, Ketteringham MA, Krauss RS (April 2003). "Promyogenic members of the Ig and cadherin families associate to positively regulate differentiation". Proceedings of the National Academy of Sciences of the United States of America. 100 (7): 3989–94. doi:10.1073/pnas.0736565100. PMC 153035. PMID 12634428.
  12. ↑ Klingelhöfer J, Troyanovsky RB, Laur OY, Troyanovsky S (August 2000). "Amino-terminal domain of classic cadherins determines the specificity of the adhesive interactions". Journal of Cell Science. 113 ( Pt 16) (16): 2829–36. PMID 10910767.
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  14. ↑ Daniel JM, Reynolds AB (September 1995). "The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or alpha-catenin". Molecular and Cellular Biology. 15 (9): 4819–24. doi:10.1128/mcb.15.9.4819. PMC 230726. PMID 7651399.
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  42. ↑ Nourry C, Maksumova L, Pang M, Liu X, Wang T (May 2004). "Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1". BMC Cell Biology. 5 (1): 20. doi:10.1186/1471-2121-5-20. PMC 420458. PMID 15144564.
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Further reading

  • Berx G, Becker KF, Höfler H, van Roy F (1998). "Mutations of the human E-cadherin (CDH1) gene". Human Mutation. 12 (4): 226–37. doi:10.1002/(SICI)1098-1004(1998)12:4<226::AID-HUMU2>3.0.CO;2-D. PMID 9744472.
  • Wijnhoven BP, Dinjens WN, Pignatelli M (August 2000). "E-cadherin-catenin cell-cell adhesion complex and human cancer". The British Journal of Surgery. 87 (8): 992–1005. doi:10.1046/j.1365-2168.2000.01513.x. PMID 10931041.
  • Beavon IR (August 2000). "The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation". European Journal of Cancer. 36 (13 Spec No): 1607–20. doi:10.1016/S0959-8049(00)00158-1. PMID 10959047.
  • Wilson PD (April 2001). "Polycystin: new aspects of structure, function, and regulation". Journal of the American Society of Nephrology. 12 (4): 834–45. PMID 11274246.
  • Chun YS, Lindor NM, Smyrk TC, Petersen BT, Burgart LJ, Guilford PJ, Donohue JH (July 2001). "Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated?". Cancer. 92 (1): 181–7. doi:10.1002/1097-0142(20010701)92:1<181::AID-CNCR1307>3.0.CO;2-J. PMID 11443625.
  • Hazan RB, Qiao R, Keren R, Badano I, Suyama K (April 2004). "Cadherin switch in tumor progression". Annals of the New York Academy of Sciences. 1014 (1): 155–63. doi:10.1196/annals.1294.016. PMID 15153430.
  • Bryant DM, Stow JL (August 2004). "The ins and outs of E-cadherin trafficking". Trends in Cell Biology. 14 (8): 427–34. doi:10.1016/j.tcb.2004.07.007. PMID 15308209.
  • Wang HD, Ren J, Zhang L (November 2004). "CDH1 germline mutation in hereditary gastric carcinoma". World Journal of Gastroenterology. 10 (21): 3088–93. PMID 15457549.
  • Reynolds AB, Carnahan RH (December 2004). "Regulation of cadherin stability and turnover by p120ctn: implications in disease and cancer". Seminars in Cell & Developmental Biology. 15 (6): 657–63. doi:10.1016/j.semcdb.2004.09.003. PMID 15561585.
  • Moran CJ, Joyce M, McAnena OJ (April 2005). "CDH1 associated gastric cancer: a report of a family and review of the literature". European Journal of Surgical Oncology. 31 (3): 259–64. doi:10.1016/j.ejso.2004.12.010. PMID 15780560.
  • Georgolios A, Batistatou A, Manolopoulos L, Charalabopoulos K (March 2006). "Role and expression patterns of E-cadherin in head and neck squamous cell carcinoma (HNSCC)". Journal of Experimental & Clinical Cancer Research. 25 (1): 5–14. PMID 16761612.
  • Renaud-Young M, Gallin WJ (October 2002). "In the first extracellular domain of E-cadherin, heterophilic interactions, but not the conserved His-Ala-Val motif, are required for adhesion". The Journal of Biological Chemistry. 277 (42): 39609–16. doi:10.1074/jbc.M201256200. PMID 12154084.

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