{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:48:48Z","timestamp":1790743728012,"version":"4.1.0"},"reference-count":41,"publisher":"The Company of Biologists","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2002,4,1]]},"abstract":"<jats:p>P120 catenin (p120ctn) belongs to the Armadillo family of proteins, which is implicated in cell-cell adhesion and signal transduction. Owing to alternative splicing and multiple translation initiation codons, several p120ctn isoforms can be expressed from a single gene. All p120ctn isoforms share the central Armadillo repeat domain but have divergent N- and C-termini. Little is known about the biological functions of the different isoforms. In this study, we examined the distribution of various p120ctn isoforms and the consequences of their expression in cultured cells of epidermal origin. Immunohistochemical analysis and western blotting revealed that melanocytes and melanoma cells primarily express the long isoform 1A, whereas keratinocytes express shorter isoforms, especially 3A, which localize to cell-cell adhesion junctions in a calcium-dependent manner. The shortest isoform 4A, which was detected in normal keratinocytes and melanocytes, was generally lost from cells derived from squamous cell carcinomas or melanomas. The C-terminal alternatively spliced exon B was present in the p120ctn transcripts in the colon, intestine and prostate, but was lost in several tumor tissues derived from these organs. To test whether p120ctn isoforms serve in distinct biological functions, we transiently transfected the expression constructs into melanoma cells (1205-Lu) and immortalized keratinocytes (HaCaT). Indeed, distinct domains of p120ctn are responsible for its different biological functions. The prominent branching phenotype was induced equally by isoforms 1A, 2A and 3A, whereas the shortest isoform 4A,which was devoid of the N-terminal domain, completely lacked this ability. Also, the exon-B-encoded sequences, as in the isoform 1AB, were sufficient to abolish the branching phenotype as induced by the isoform 1A. The induction of the branching phenotype cosegregated with the nuclear localization of the p120ctn isoforms 1A, 2A and 3A, whereas the isoforms 4A and 1AB, which were excluded from the nucleus, did not induce the branching phenotype. The N-terminal sequences that contain seven out of eight tyrosine residues,recently characterized as potential candidates for phosphorylation by Src kinase, are required for the nuclear localization and for the formation of the branching phenotype. Finally, expression of the p120ctn isoforms, which caused the branching phenotype, was associated with cellular relocalization of E-cadherin in HaCaT cells. Collectively, we have identified sequences within the p120ctn N-terminus that are prerequisites for both nuclear localization and the p120ctn-induced branching phenotype. Loss of the cytoplasmic pool of p120ctn from tumor cells suggests an important function for such isoforms in normal cells and tissues.<\/jats:p>","DOI":"10.1242\/jcs.115.7.1391","type":"journal-article","created":{"date-parts":[[2021,4,24]],"date-time":"2021-04-24T06:47:54Z","timestamp":1619246874000},"page":"1391-1402","source":"Crossref","is-referenced-by-count":66,"title":["Specific sequences in p120ctn determine subcellular distribution of its multiple isoforms involved in cellular adhesion of normal and malignant epithelial cells"],"prefix":"10.1242","volume":"115","author":[{"given":"Sirpa","family":"Aho","sequence":"first","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Leva\u0308nsuo","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"Montonen","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csaba","family":"Kari","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Rodeck","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jouni","family":"Uitto","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042517350150700_REF1","doi-asserted-by":"crossref","unstructured":"Aho, S., Rothenberger, K. and Uitto, J. (1999). Human p120(ctn) catenin: Tissue-specific expression of isoforms and molecular interactions with BP180\/ type XVII collagen. J. Cell. Biochem.73, 390-399.","DOI":"10.1002\/(SICI)1097-4644(19990601)73:3<390::AID-JCB10>3.0.CO;2-1"},{"key":"2021042517350150700_REF2","doi-asserted-by":"crossref","unstructured":"Aho, S., Buisson, M., Pajunen, T., Ryoo, Y. W., Giot, J.-F.,Gruffat, H., Sergeant, A. and Uitto, J. (2000). Ubinuclein, a novel nuclear protein interacting with cellular and viral transcription factors. J. Cell Biol.148, 1165-1176.","DOI":"10.1083\/jcb.148.6.1165"},{"key":"2021042517350150700_REF3","doi-asserted-by":"crossref","unstructured":"Anastasiadis, P. Z. and Reynolds, A. B. (2000). The p120 catenin family: complex roles in adhesion, signaling and cancer.J. Cell. Sci.113, 1319-1334.","DOI":"10.1242\/jcs.113.8.1319"},{"key":"2021042517350150700_REF4","doi-asserted-by":"crossref","unstructured":"Anastasiadis, P. Z., Moon, S. Y., Thoreson, M. A., Mariner, D. J., Crawford, H. C., Zheng, Y. and Reynolds, A. B. (2000). Inhibition of RhoA by p120 catenin. Nat. Cell. Biol.2, 637-644.","DOI":"10.1038\/35023588"},{"key":"2021042517350150700_REF5","doi-asserted-by":"crossref","unstructured":"Aono, S., Nakagawa, S., Reynolds, A. B. and Takeichi, M.(1999). p120(ctn) acts as an inhibitory regulator of cadherin function in colon carcinoma cells. J. Cell Biol.145, 551-562.","DOI":"10.1083\/jcb.145.3.551"},{"key":"2021042517350150700_REF6","doi-asserted-by":"crossref","unstructured":"Behrens, J., von Kries, J. P., Ku\u0308hl, M., Bruhn, L.,Wedlich, D., Grosschedl, R. and Birchmeier, W. (1996). Functional interaction of \u03b2-catenin with the transcription factor LEF-1.Nature382, 638-642.","DOI":"10.1038\/382638a0"},{"key":"2021042517350150700_REF7","doi-asserted-by":"crossref","unstructured":"Boukamp, P., Petrussevska, R. T., Breitkreutz, D., Hornung, J.,Markham, A. and Fusenig, N. E. (1988). Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line.J. Cell Biol.106, 761-771.","DOI":"10.1083\/jcb.106.3.761"},{"key":"2021042517350150700_REF8","doi-asserted-by":"crossref","unstructured":"Braga, V. (2000). Epithelial cell shape:cadherins and small GTPases. Exp. Cell Res.261, 83-90.","DOI":"10.1006\/excr.2000.5050"},{"key":"2021042517350150700_REF9","doi-asserted-by":"crossref","unstructured":"Calautti, E., Cabodi, S., Stein, P. L., Hatzfeld, M., Kedersha,N. and Dotto, G. P. (1998). Tyrosine phosphorylation and Scr family kinases control keratinocyte cell-cell adhesion. J. Cell Biol.141, 1449-1465.","DOI":"10.1083\/jcb.141.6.1449"},{"key":"2021042517350150700_REF10","doi-asserted-by":"crossref","unstructured":"Daniel, J. M. and Reynolds, A. B. (1995). The tyrosine kinase substrate p120cas binds directly to E-cadherin but not to the adenomatous polyposis coli protein or \u03b1-catenin. Mol. Cell. 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Genomics50, 129-146.","DOI":"10.1006\/geno.1998.5325"},{"key":"2021042517350150700_REF17","doi-asserted-by":"crossref","unstructured":"Kim, L. and Wong, T. W. (1995). The cytoplasmic tyrosine kinase FER is associated with the catenin-like substrate pp120 and is activated by growth factors. Mol. Cell. Biol.15, 4553-4561.","DOI":"10.1128\/MCB.15.8.4553"},{"key":"2021042517350150700_REF18","doi-asserted-by":"crossref","unstructured":"Mariner, D. J., Anastasiadis, P., Keilhack, H., Bo\u0308hmer,F.-D., Wang, J. and Reynolds, A. (2001). Identification of Src phosphorylation sites in the catenin p120ctn. J. Biol. Chem.276, 28006-28013.","DOI":"10.1074\/jbc.M102443200"},{"key":"2021042517350150700_REF19","unstructured":"Melber, K., Zhu, G. and Diamond, L. (1989). SV-40-transfected human melanocyte sensitivity to growth inhibition by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Cancer Res.49, 3650-3655."},{"key":"2021042517350150700_REF20","unstructured":"Mo, Y.-Y. and Reynolds, A. B. (1996). Identification of murine p120cas isoforms and heterogeneous expression of p120cas isoforms in human tumor cell lines. Cancer Res.56, 2633-2640."},{"key":"2021042517350150700_REF21","doi-asserted-by":"crossref","unstructured":"Montonen, O., Aho, M., Uitto, J. and Aho, S.(2001). Tissue distribution and cell type-specific expression of p120ctn isoforms. J. Histochem. Cytochem.49, 1487-1495.","DOI":"10.1177\/002215540104901202"},{"key":"2021042517350150700_REF22","doi-asserted-by":"crossref","unstructured":"Nobes, C. D. and Hall, A. (1995). Rho, rac and cdc42 GTPases: regulators of actin structures, cell adhesion and motility.Biochem. Soc. Trans.23, 456-459.","DOI":"10.1042\/bst0230456"},{"key":"2021042517350150700_REF23","doi-asserted-by":"crossref","unstructured":"Nollet, F., Berx, G. and van Roy, F. (1999). The role of the E-cadherin\/Catenin adhesion complex in the development and progression of cancer. Mol. Cell. Biol. Res. 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Association of p120, a tyrosine kinase substrate, with E-cadherin\/catenin complexes. J. Cell Biol.128, 949-957.","DOI":"10.1083\/jcb.128.5.949"},{"key":"2021042517350150700_REF36","doi-asserted-by":"crossref","unstructured":"Staddon, J. M., Smales, C., Schulze, C., Esch, F. S. and Rubin,L. L. (1995). p120, a p120-related protein (p100), and the cadherin\/catenin complex. J. Cell Biol.130, 369-381.","DOI":"10.1083\/jcb.130.2.369"},{"key":"2021042517350150700_REF37","doi-asserted-by":"crossref","unstructured":"Thoreson, M. A., Anastasiadis, P. Z., Daniel, J. M., Ireton, R. C., Wheelock, M. J., Johnson, K. R., Hummingbird, D. K. and Reynolds, A. B. (2000). Selective uncoupling of p120ctn from E-cadherin disrupts strong adhesion. J. Cell Biol.148, 189-201.","DOI":"10.1083\/jcb.148.1.189"},{"key":"2021042517350150700_REF38","doi-asserted-by":"crossref","unstructured":"van Hengel, J., Vanhoenacker, P., Staes, K. and van Roy, F.(1999). Nuclear localization of the p120ctn Armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression. Proc. Natl. Acad. Sci. USA96, 7980-7985.","DOI":"10.1073\/pnas.96.14.7980"},{"key":"2021042517350150700_REF39","doi-asserted-by":"crossref","unstructured":"Wu, J., Mariner, D. J., Thoreson, M. A. and Reynolds, A. B.(1998). Production and characterization of monoclonal antibodies to the catenin p120ctn. Hybridoma17, 175-183.","DOI":"10.1089\/hyb.1998.17.175"},{"key":"2021042517350150700_REF40","doi-asserted-by":"crossref","unstructured":"Yap, A. S., Niessen, C. M. and Gumbiner, B. M.(1998). The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn. J. Cell Biol.141, 779-789.","DOI":"10.1083\/jcb.141.3.779"},{"key":"2021042517350150700_REF41","doi-asserted-by":"crossref","unstructured":"Zondag, G. C. M., Reynolds, A. B. and Moolenaar, W. H.(2000). Receptor protein-tyrosine phosphatase RPTP\u03bc binds to and dephosphorylates the catenin p120ctn. J. Biol. 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