Catenin alpha-1 explained

αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene.^{[1] [2]} αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.

Structure

Human αE-catenin protein is 100.0 kDa and 906 amino acids.^[3] Catenins (α,β,and γ (also known as plakoglobin)) were originally identified in complex with E-cadherin, an epithelial cell adhesion protein. αE-catenin is highly expressed in cardiac muscle^{[4] [5]} and is homologous to the protein vinculin; however, aside from vinculin, αE-catenin has no homology to established actin-binding proteins. The N-terminus of αE-catenin binds β-catenin or γ-catenin/plakoglobin, and the C-terminus binds actin directly or indirectly via vinculin or α-actinin.^[6]

Function

Though αE-catenin exhibits substantial expression in cardiac muscle, αE-catenin is most well known for role in metastasizing tumor cells.^[7] αE-catenin also plays a role in epithelial tissue, both at adherens junctions and in signaling pathways.^[8]

In cardiomyocytes, αE-catenin is present in cell to cell regions known as adherens junctions which lie within intercalated discs; these junctions anchor the actin cytoskeleton to the sarcolemma and provide strong cell adhesion.^[9]

Functional αE-catenin is required for normal embryonic development, as a mutation eliminating the C-terminal 1/3 of the protein resulting in a complete loss-of-function phenotype showed disruption of the trophoblast epithelium and arrested development at the blastocyst stage.^[10]

αE-catenin specifically, not β- or γ-catenin, binds F-actin and organizes and tethers the filaments at regions of cell-cell contact. Studies show that full-length αE-catenin binds and bundles F-actin in a superior fashion relative to individual N-terminal or C-terminal domains.^[11]

αE-catenin, along with β-catenin and plakoglobin form distinct complexes with N-cadherin that are involved in forming cell-cell contacts and differentiation of cardiomyocytes. Catenin-N-cadherin complexes are apparently necessary for and precede the first cell to cell contact, precursory to gap junction formation.^[12] The anchorage of cadherin-catenin complexes to actin filaments by αE-catenin is regulated by tyrosine phosphorylation.^[13]

Functional insights into αE-catenin function have come from studies employing transgenesis. Mice harboring a cardiac-specific deletion of αE-catenin exhibited abnormalities in cardiac dimensions and function, representative of dilated cardiomyopathy. This was further characterized by disorganization of intercalated disc structures and mitochondria, as well as compensatory increases in β-catenin and decreases in localization of cadherin and vinculin at intercalated discs. Knockout mice also exhibited high susceptibility to death following stress.^[14]

Interactions

αE-catenin has been shown to interact with:

• APC,^{[15] [16]}
• Beta-catenin,^{[17] [18] [19] [20] [21]}
• CDH1,^{[22] [23] [24] [25] [26]}
• CDH2,^{[27] [28]}
• CDH3^{[26] [29]}
• Plakoglobin,^{[18] [30] [31]} and
• VE-cadherin.^{[32] [33]}

See also

• Alpha-catenin

Further reading

• Nagafuchi A, Takeichi M, Tsukita S . The 102 kd cadherin-associated protein: similarity to vinculin and posttranscriptional regulation of expression. . Cell . 65 . 5 . 849–57 . 1991 . 1904011 . 10.1016/0092-8674(91)90392-C . 38622586 .
• Kinch MS, Clark GJ, Der CJ, Burridge K . Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia. . J. Cell Biol. . 130 . 2 . 461–71 . 1995 . 7542250 . 2199929 . 10.1083/jcb.130.2.461 .
• Sacco PA, McGranahan TM, Wheelock MJ, Johnson KR . Identification of plakoglobin domains required for association with N-cadherin and alpha-catenin. . J. Biol. Chem. . 270 . 34 . 20201–6 . 1995 . 7650039 . 10.1074/jbc.270.34.20201 . free .
• Daniel JM, Reynolds AB . The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or alpha-catenin. . Mol. Cell. Biol. . 15 . 9 . 4819–24 . 1995 . 7651399 . 230726 . 10.1128/mcb.15.9.4819.
• Aberle H, Butz S, Stappert J, Weissig H, Kemler R, Hoschuetzky H . Assembly of the cadherin-catenin complex in vitro with recombinant proteins. . J. Cell Sci. . 107 . 12 . 3655–63 . 1995 . 10.1242/jcs.107.12.3655 . 7706414 .
• Knudsen KA, Soler AP, Johnson KR, Wheelock MJ . Interaction of alpha-actinin with the cadherin/catenin cell-cell adhesion complex via alpha-catenin. . J. Cell Biol. . 130 . 1 . 67–77 . 1995 . 7790378 . 2120515 . 10.1083/jcb.130.1.67 .
• Rimm DL, Kebriaei P, Morrow JS . Molecular cloning reveals alternative splice forms of human alpha(E)-catenin. . Biochem. Biophys. Res. Commun. . 203 . 3 . 1691–9 . 1994 . 7945318 . 10.1006/bbrc.1994.2381 . free .
• Oyama T, Kanai Y, Ochiai A, Akimoto S, Oda T, Yanagihara K, Nagafuchi A, Tsukita S, Shibamoto S, Ito F . 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. . Cancer Res. . 54 . 23 . 6282–7 . 1994 . 7954478 .
• McPherson JD, Morton RA, Ewing CM, Wasmuth JJ, Overhauser J, Nagafuchi A, Tsukita S, Isaacs WB . Assignment of the human alpha-catenin gene (CTNNA1) to chromosome 5q21-q22. . Genomics . 19 . 1 . 188–90 . 1994 . 8188230 . 10.1006/geno.1994.1042 . free .
• Su LK, Vogelstein B, Kinzler KW . Association of the APC tumor suppressor protein with catenins. . Science . 262 . 5140 . 1734–7 . 1994 . 8259519 . 10.1126/science.8259519 . 1993Sci...262.1734S .
• Oda T, Kanai Y, Shimoyama Y, Nagafuchi A, Tsukita S, Hirohashi S . Cloning of the human alpha-catenin cDNA and its aberrant mRNA in a human cancer cell line. . Biochem. Biophys. Res. Commun. . 193 . 3 . 897–904 . 1993 . 8323564 . 10.1006/bbrc.1993.1710 .
• Furukawa Y, Nakatsuru S, Nagafuchi A, Tsukita S, Muto T, Nakamura Y, Horii A . Structure, expression and chromosome assignment of the human catenin (cadherin-associated protein) alpha 1 gene (CTNNA1). . Cytogenet. Cell Genet. . 65 . 1–2 . 74–8 . 1993 . 8404069 . 10.1159/000133603 .
• Obama H, Ozawa M . Identification of the domain of alpha-catenin involved in its association with beta-catenin and plakoglobin (gamma-catenin). . J. Biol. Chem. . 272 . 17 . 11017–20 . 1997 . 9110993 . 10.1074/jbc.272.17.11017 . free .
• Linkels M, Bussemakers MJ, Nollet F, Ewing CM, van Roy F, Schalken JA . Molecular cloning of an alternative human alphaE-catenin cDNA. . Biochem. Biophys. Res. Commun. . 237 . 1 . 177–81 . 1997 . 9266853 . 10.1006/bbrc.1997.7058 . free .
• Lewalle JM, Bajou K, Desreux J, Mareel M, Dejana E, Noël A, Foidart JM . Alteration of interendothelial adherens junctions following tumor cell-endothelial cell interaction in vitro. . Exp. Cell Res. . 237 . 2 . 347–56 . 1998 . 9434630 . 10.1006/excr.1997.3799 . 2268/61990 . free .
• Reuver SM, Garner CC . E-cadherin mediated cell adhesion recruits SAP97 into the cortical cytoskeleton. . J. Cell Sci. . 111 . 8 . 1071–80 . 1998 . 10.1242/jcs.111.8.1071 . 9512503 .
• Watabe-Uchida M, Uchida N, Imamura Y, Nagafuchi A, Fujimoto K, Uemura T, Vermeulen S, van Roy F, Adamson ED, Takeichi M . alpha-Catenin-vinculin interaction functions to organize the apical junctional complex in epithelial cells. . J. Cell Biol. . 142 . 3 . 847–57 . 1998 . 9700171 . 2148175 . 10.1083/jcb.142.3.847 .
• Roe S, Koslov ER, Rimm DL . A mutation in alpha-catenin disrupts adhesion in clone A cells without perturbing its actin and beta-catenin binding activity. . Cell Adhes. Commun. . 5 . 4 . 283–96 . 1998 . 9762469 . 10.3109/15419069809040298 . free .
• Itoh M, Morita K, Tsukita S . Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha catenin. . J. Biol. Chem. . 274 . 9 . 5981–6 . 1999 . 10026224 . 10.1074/jbc.274.9.5981 . free .

Notes and References

1. Herrenknecht K, Ozawa M, Eckerskorn C, Lottspeich F, Lenter M, Kemler R . The uvomorulin-anchorage protein alpha-catenin is a vinculin homologue . Proc Natl Acad Sci U S A . 88 . 20 . 9156–60 . November 1991 . 1924379 . 52671 . 10.1073/pnas.88.20.9156 . 1991PNAS...88.9156H . free .
2. Web site: Entrez Gene: CTNNA1 catenin (cadherin-associated protein), alpha 1, 102kDa.
3. Web site: Protein sequence of human CTNNA1 (Uniprot ID: P35221). Cardiac Organellar Protein Atlas Knolwedgebase (COPaKB). 3 July 2015. https://web.archive.org/web/20150704094841/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P35221. 4 July 2015. dead.
4. Janssens B, Goossens S, Staes K, Gilbert B, van Hengel J, Colpaert C, Bruyneel E, Mareel M, van Roy F . alphaT-catenin: a novel tissue-specific beta-catenin-binding protein mediating strong cell-cell adhesion . Journal of Cell Science . 114 . Pt 17 . 3177–88 . Sep 2001 . 10.1242/jcs.114.17.3177 . 11590244 .
5. Ehler E, Horowits R, Zuppinger C, Price RL, Perriard E, Leu M, Caroni P, Sussman M, Eppenberger HM, Perriard JC . Alterations at the intercalated disk associated with the absence of muscle LIM protein . The Journal of Cell Biology . 153 . 4 . 763–72 . May 2001 . 11352937 . 10.1083/jcb.153.4.763 . 2192386.
6. Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI . Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly . Cell . 123 . 5 . 903–15 . Dec 2005 . 16325583 . 10.1016/j.cell.2005.09.021 . 3369825.
7. Breen E, Clarke A, Steele G, Mercurio AM . Poorly differentiated colon carcinoma cell lines deficient in alpha-catenin expression express high levels of surface E-cadherin but lack Ca(2+)-dependent cell-cell adhesion . Cell Adhesion and Communication . 1 . 3 . 239–50 . Dec 1993 . 8081881 . 10.3109/15419069309097257.
8. Vasioukhin V, Bauer C, Degenstein L, Wise B, Fuchs E . Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin . Cell . 104 . 4 . 605–17 . Feb 2001 . 11239416 . 10.1016/s0092-8674(01)00246-x. 6029663 . free .
9. Jamora C, Fuchs E . Intercellular adhesion, signalling and the cytoskeleton . Nature Cell Biology . 4 . 4 . E101–8 . Apr 2002 . 11944044 . 10.1038/ncb0402-e101 . 22314929 .
10. Torres M, Stoykova A, Huber O, Chowdhury K, Bonaldo P, Mansouri A, Butz S, Kemler R, Gruss P . An alpha-E-catenin gene trap mutation defines its function in preimplantation development . Proceedings of the National Academy of Sciences of the United States of America . 94 . 3 . 901–6 . Feb 1997 . 9023354 . 10.1073/pnas.94.3.901 . 19611. 1997PNAS...94..901T . free .
11. Rimm DL, Koslov ER, Kebriaei P, Cianci CD, Morrow JS . Alpha 1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex . Proceedings of the National Academy of Sciences of the United States of America . 92 . 19 . 8813–7 . Sep 1995 . 7568023 . 10.1073/pnas.92.19.8813 . 41057. 1995PNAS...92.8813R . free .
12. Hertig CM, Butz S, Koch S, Eppenberger-Eberhardt M, Kemler R, Eppenberger HM . N-cadherin in adult rat cardiomyocytes in culture. II. Spatio-temporal appearance of proteins involved in cell-cell contact and communication. Formation of two distinct N-cadherin/catenin complexes . Journal of Cell Science . 109 . 11–20 . Jan 1996 . 8834786 . 1. 10.1242/jcs.109.1.11 .
13. Aberle H, Schwartz H, Kemler R . Cadherin-catenin complex: protein interactions and their implications for cadherin function . Journal of Cellular Biochemistry . 61 . 4 . 514–23 . Jun 1996 . 8806074 . 10.1002/(SICI)1097-4644(19960616)61:4<514::AID-JCB4>3.0.CO;2-R . 24566745 .
14. Sheikh F, Chen Y, Chen Y, Liang X, Hirschy A, Stenbit AE, Gu Y, Dalton ND, Yajima T, Lu Y, Knowlton KU, Peterson KL, Perriard JC, Chen J . alpha-E-catenin inactivation disrupts the cardiomyocyte adherens junction, resulting in cardiomyopathy and susceptibility to wall rupture . Circulation . 114 . 10 . 1046–55 . Sep 2006 . 16923756 . 10.1161/CIRCULATIONAHA.106.634469 . free .
15. Su LK, Vogelstein B, Kinzler KW . Association of the APC tumor suppressor protein with catenins . Science . 262 . 5140 . 1734–7 . December 1993 . 8259519 . 10.1126/science.8259519. 1993Sci...262.1734S .
16. Daniel JM, Reynolds AB . The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or alpha-catenin . Mol. Cell. Biol. . 15 . 9 . 4819–24 . September 1995 . 7651399 . 230726 . 10.1128/mcb.15.9.4819.
17. Oyama T, Kanai Y, Ochiai A, Akimoto S, Oda T, Yanagihara K, Nagafuchi A, Tsukita S, Shibamoto S, Ito F . 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 . Cancer Res. . 54 . 23 . 6282–7 . December 1994 . 7954478 .
18. Roe S, Koslov ER, Rimm DL . A mutation in alpha-catenin disrupts adhesion in clone A cells without perturbing its actin and beta-catenin binding activity . Cell Adhes. Commun. . 5 . 4 . 283–96 . June 1998 . 9762469 . 10.3109/15419069809040298. free .
19. Piedra J, Miravet S, Castaño J, Pálmer HG, Heisterkamp N, García de Herreros A, Duñach M . p120 Catenin-associated Fer and Fyn tyrosine kinases regulate beta-catenin Tyr-142 phosphorylation and beta-catenin-alpha-catenin Interaction . Mol. Cell. Biol. . 23 . 7 . 2287–97 . April 2003 . 12640114 . 150740 . 10.1128/mcb.23.7.2287-2297.2003.
20. Aberle H, Butz S, Stappert J, Weissig H, Kemler R, Hoschuetzky H . Assembly of the cadherin-catenin complex in vitro with recombinant proteins . J. Cell Sci. . 107 . 12. 3655–63 . December 1994 . 10.1242/jcs.107.12.3655 . 7706414 .
21. Reuver SM, Garner CC . E-cadherin mediated cell adhesion recruits SAP97 into the cortical cytoskeleton . J. Cell Sci. . 111 . 8. 1071–80 . April 1998 . 10.1242/jcs.111.8.1071 . 9512503 .
22. Kinch MS, Clark GJ, Der CJ, Burridge K . Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia . J. Cell Biol. . 130 . 2 . 461–71 . July 1995 . 7542250 . 2199929 . 10.1083/jcb.130.2.461.
23. Oneyama C, Nakano H, Sharma SV . UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug . Oncogene . 21 . 13 . 2037–50 . March 2002 . 11960376 . 10.1038/sj.onc.1205271 . free .
24. Navarro P, Lozano E, Cano A . 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 . J. Cell Sci. . 105 . 4. 923–34 . August 1993 . 10.1242/jcs.105.4.923 . 8227214 . 10261/78716 . free .
25. Takahashi K, Suzuki K, Tsukatani Y . Induction of tyrosine phosphorylation and association of beta-catenin with EGF receptor upon tryptic digestion of quiescent cells at confluence . Oncogene . 15 . 1 . 71–8 . July 1997 . 9233779 . 10.1038/sj.onc.1201160 . free .
26. Schmeiser K, Grand RJ . The fate of E- and P-cadherin during the early stages of apoptosis . Cell Death Differ. . 6 . 4 . 377–86 . April 1999 . 10381631 . 10.1038/sj.cdd.4400504 . free .
27. Straub BK, Boda J, Kuhn C, Schnoelzer M, Korf U, Kempf T, Spring H, Hatzfeld M, Franke WW . A novel cell-cell junction system: the cortex adhaerens mosaic of lens fiber cells . J. Cell Sci. . 116 . Pt 24 . 4985–95 . December 2003 . 14625392 . 10.1242/jcs.00815 . free .
28. Wahl JK, Kim YJ, Cullen JM, Johnson KR, Wheelock MJ . N-cadherin-catenin complexes form prior to cleavage of the proregion and transport to the plasma membrane . J. Biol. Chem. . 278 . 19 . 17269–76 . May 2003 . 12604612 . 10.1074/jbc.M211452200 . free .
29. Klingelhöfer J, Troyanovsky RB, Laur OY, Troyanovsky S . Amino-terminal domain of classic cadherins determines the specificity of the adhesive interactions . J. Cell Sci. . 113 . 16. 2829–36 . August 2000 . 10.1242/jcs.113.16.2829 . 10910767 .
30. Sacco PA, McGranahan TM, Wheelock MJ, Johnson KR . Identification of plakoglobin domains required for association with N-cadherin and alpha-catenin . J. Biol. Chem. . 270 . 34 . 20201–6 . August 1995 . 7650039 . 10.1074/jbc.270.34.20201. free .
31. Obama H, Ozawa M . Identification of the domain of alpha-catenin involved in its association with beta-catenin and plakoglobin (gamma-catenin) . J. Biol. Chem. . 272 . 17 . 11017–20 . April 1997 . 9110993 . 10.1074/jbc.272.17.11017. free .
32. Lewalle JM, Bajou K, Desreux J, Mareel M, Dejana E, Noël A, Foidart JM . Alteration of interendothelial adherens junctions following tumor cell-endothelial cell interaction in vitro . Exp. Cell Res. . 237 . 2 . 347–56 . December 1997 . 9434630 . 10.1006/excr.1997.3799 . 2268/61990 . free .
33. Shasby DM, Ries DR, Shasby SS, Winter MC . Histamine stimulates phosphorylation of adherens junction proteins and alters their link to vimentin . Am. J. Physiol. Lung Cell Mol. Physiol. . 282 . 6 . L1330–8 . June 2002 . 12003790 . 10.1152/ajplung.00329.2001 . 10.1.1.1000.5266 .