Phosphorylation of β-Catenin by AKT Promotes β-Catenin Transcriptional ActivityDexing Fang, David H. Hawke, Yanhua Zheng et al.|Journal of Biological Chemistry|2007 Increased transcriptional activity of β-catenin resulting from Wnt/Wingless-dependent or -independent signaling has been detected in many types of human cancer, but the underlying mechanism of Wnt-independent regulation is poorly understood. We have demonstrated that AKT, which is activated downstream from epidermal growth factor receptor signaling, phosphorylates β-catenin at Ser552 in vitro and in vivo. AKT-mediated phosphorylation of β-catenin causes its disassociation from cell-cell contacts and accumulation in both the cytosol and the nucleus and enhances its interaction with 14-3-3ζ via a binding motif containing Ser552. Phosphorylation of β-catenin by AKT increases its transcriptional activity and promotes tumor cell invasion, indicating that AKT-dependent regulation of β-catenin plays a critical role in tumor invasion and development. Increased transcriptional activity of β-catenin resulting from Wnt/Wingless-dependent or -independent signaling has been detected in many types of human cancer, but the underlying mechanism of Wnt-independent regulation is poorly understood. We have demonstrated that AKT, which is activated downstream from epidermal growth factor receptor signaling, phosphorylates β-catenin at Ser552 in vitro and in vivo. AKT-mediated phosphorylation of β-catenin causes its disassociation from cell-cell contacts and accumulation in both the cytosol and the nucleus and enhances its interaction with 14-3-3ζ via a binding motif containing Ser552. Phosphorylation of β-catenin by AKT increases its transcriptional activity and promotes tumor cell invasion, indicating that AKT-dependent regulation of β-catenin plays a critical role in tumor invasion and development. β-Catenin, originally identified as a component of cell-cell adhesion structures, interacts with the cytoplasmic domain of E-cadherin and links E-cadherin to α-catenin, which in turn mediates anchorage of the E-cadherin complex to the cortical actin cytoskeleton (1Rimm D.L. Koslov E.R. Kebriaei P. Cianci C.D. Morrow J.S. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8813-8817Crossref PubMed Scopus (633) Google Scholar, 2Vasioukhin V. Fuchs E. Curr. Opin. Cell Biol. 2001; 13: 76-84Crossref PubMed Scopus (243) Google Scholar, 3Nagafuchi A. Curr. Opin. Cell Biol. 2001; 13: 600-603Crossref PubMed Scopus (258) Google Scholar). Genetic and embryologic studies have revealed that β-catenin is also a component of the Wnt signaling pathway and that it exhibits signaling functions (4Kikuchi A. Cancer Sci. 2003; 94: 225-229Crossref PubMed Scopus (201) Google Scholar). In the absence of a Wnt/Wingless signal, cytoplasmic β-catenin interacts with axin/conductin, glycogen synthase kinase-3β (GSK-3β), 3The abbreviations used are: GSK-3β, glycogen synthase kinase-3β; TCF/LEF-1, T-cell factor/lymphoid enhancer factor 1; EGF, epidermal growth factor; EGFR, EGF receptor; CHO, Chinese hamster ovary; HA, hemagglutinin; WT, wild type; PKA, cAMP-dependent protein kinase. and the adenomatous polyposis coli (APC) protein, which competes with E-cadherin for binding to the armadillo-like repeats of β-catenin (5Hulsken J. Birchmeier W. Behrens J. J. Cell Biol. 1994; 127: 2061-2069Crossref PubMed Scopus (585) Google Scholar). β-Catenin is phosphorylated in its N-terminal domain by GSK-3β, which leads to its degradation via the ubiquitin/proteasome pathway mediated by SKP1/CUL1/F-box E3 ligase (6Aberle H. Bauer A. Stappert J. Kispert A. Kemler R. EMBO J. 1997; 16: 3797-3804Crossref PubMed Scopus (2160) Google Scholar, 7Orford K. Orford C.C. Byers S.W. J. Cell Biol. 1999; 146: 855-868Crossref PubMed Scopus (238) Google Scholar, 8Rubinfeld B. Albert I. Porfiri E. Fiol C. Munemitsu S. Polakis P. Science. 1996; 272: 1023-1026Crossref PubMed Scopus (1301) Google Scholar, 9Yost C. Torres M. Miller J.R. Huang E. Kimelman D. Moon R.T. Genes Dev. 1996; 10: 1443-1454Crossref PubMed Scopus (1018) Google Scholar, 10Behrens J. Jerchow B.A. Wurtele M. Grimm J. Asbrand C. Wirtz R. Kuhl M. Wedlich D. Birchmeier W. Science. 1998; 280: 596-599Crossref PubMed Scopus (1113) Google Scholar, 11Ikeda S. Kishida S. Yamamoto H. Murai H. Koyama S. Kikuchi A. EMBO J. 1998; 17: 1371-1384Crossref PubMed Scopus (1101) Google Scholar). Activation of the Wnt/Wingless pathway inhibits GSK-3β-dependent phosphorylation of β-catenin. Stabilized, hypophosphorylated β-catenin translocates to the nucleus, where it interacts with transcription factors of the TCF/LEF-1 family, leading to the increased expression of genes, such as MYC and CCND1 (12He T.C. Sparks A.B. Rago C. Hermeking H. Zawel L. da Costa L.T. Morin P.J. Vogelstein B. Kinzler K.W. Science. 1998; 281: 1509-1512Crossref PubMed Scopus (4084) Google Scholar, 13Tetsu O. McCormick F. Nature. 1999; 398: 422-426Crossref PubMed Scopus (3259) Google Scholar, 14Shtutman M. Zhurinsky J. Simcha I. Albanese C. D'Amico M. Pestell R. Ben-Ze'ev A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 5522-5527Crossref PubMed Scopus (1919) Google Scholar). Hepatocyte growth factor and epidermal growth factor (EGF) induce β-catenin signaling under conditions where they stimulate cell motility (15Muller T. Bain G. Wang X. Papkoff J. Exp. Cell Res. 2002; 280: 119-133Crossref PubMed Scopus (153) Google Scholar, 16Lu Z. Ghosh S. Wang Z. Hunter T. Cancer Cell. 2003; 4: 499-515Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar). Gain of function mutations in β-catenin, including N-terminal mutations that lead to stabilization of the protein or loss of function mutations in proteins that participate in the regulated turnover of β-catenin, such as the tumor suppressor APC, result in up-regulation of β-catenin protein levels, thus increasing its transcriptional activity. Increased β-catenin-TCF/LEF-1 transactivation by enhanced β-catenin stability, resulting from mutations in APC, AXIN1, or CTNNB1 (which encodes β-catenin), is found in a wide variety of human cancers, including colon cancer, desmoid tumor, gastric cancer, hepatocarcinoma, medulloblastoma, melanoma, ovarian cancer, pancreatic cancer, and prostate cancer (17Polakis P. Genes Dev. 2000; 14: 1837-1851Crossref PubMed Google Scholar, 18Peifer M. Polakis P. Science. 2000; 287: 1606-1609Crossref PubMed Scopus (1143) Google Scholar, 19Morin P.J. BioEssays. 1999; 21: 1021-1030Crossref PubMed Scopus (815) Google Scholar). Mutations of Wnt pathway proteins that alter the stability of β-catenin are not the only factor that contributes to β-catenin activation. For instance, in 12 of 20 (60.0%) endometrial cancers, β-catenin was found to accumulate in the nucleus, which is a hallmark of β-catenin activation, whereas there were only two instances of mutations in the CTNNB1 gene (20Ashihara K. Saito T. Mizumoto H. Nishimura M. Tanaka R. Kudo R. Med. Electron Microsc. 2002; 35: 9-15Crossref PubMed Scopus (35) Google Scholar). Similarly, only 1 of 65 primary melanomas had detectable CTNNB1 mutations, with a third of the cases displaying nuclear accumulation of β-catenin (21Rimm D.L. Caca K. Hu G. Harrison F.B. Fearon E.R. Am. J. Pathol. 1999; 154: 325-329Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). Moreover, nearly 50% of hepatocellular carcinomas, in which the APC gene is rarely mutated, reveal nuclear accumulation of β-catenin protein, and genetic alterations in CTNNB1 are detected only in 16–26% of the tumors (22de La Coste A. Romagnolo B. Billuart P. Renard C.A. Buendia M.A. Soubrane O. Fabre M. Chelly J. Beldjord C. Kahn A. Perret C. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 8847-8851Crossref PubMed Scopus (983) Google Scholar, 23Satoh S. Daigo Y. Furukawa Y. Kato T. Miwa N. Nishiwaki T. Kawasoe T. Ishiguro H. Fujita M. Tokino T. Sasaki Y. Imaoka S. Murata M. Shimano T. Yamaoka Y. Nakamura Y. Nat. Genet. 2000; 24: 245-250Crossref PubMed Scopus (837) Google Scholar, 24Miyoshi Y. Iwao K. Nagasawa Y. Aihara T. Sasaki Y. Imaoka S. Murata M. Shimano T. Nakamura Y. Cancer Res. 1998; 58: 2524-2527PubMed Google Scholar, 25Ihara A. Koizumi H. Hashizume R. Uchikoshi T. Hepatology. 1996; 23: 1441-1447PubMed Google Scholar). Clearly, more than one mechanism regulates the activity of β-catenin (26Lu Z. Hunter T. Cell Cycle. 2004; 3: 571-573Crossref PubMed Google Scholar). In response to EGF stimulation, β-catenin translocates into the nucleus and increases its transactivation without altering its stability and phosphorylation level by GSK-3β (16Lu Z. Ghosh S. Wang Z. Hunter T. Cancer Cell. 2003; 4: 499-515Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar). Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis chronic myelogenous leukemia have high nuclear β-catenin accumulation presumably, driven by Bcr-Abl (27Jamieson C.H. Ailles L.E. Dylla S.J. Muijtjens M. Jones C. Zehnder J.L. Gotlib J. Li K. Manz M.G. Keating A. Sawyers C.L. Weissman I.L. N. Engl. J. Med. 2004; 351: 657-667Crossref PubMed Scopus (1266) Google Scholar). In this report, we demonstrate that AKT phosphorylates β-catenin at Ser552, which leads to its disassociation from cell-cell contacts, increases its binding to 14-3-3ζ and its transcriptional activity and enhances invasion by tumor cells. Cells and Cell Culture Conditions—A431 human epidermoid carcinoma cells, CHO AA8 cells, and 293T cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% bovine calf serum (HyClone, Logan, UT). Cell cultures were made quiescent by growing them to confluence and then replacing the medium with fresh medium containing 0.5% serum for 1 day. Materials—Rabbit monoclonal antibody recognizing phosphorylated RRX(S/T) peptide was obtained from Cell Signaling Technology (Danvers, MA). Polyclonal antibody for 14-3-3ζ and monoclonal antibodies for β-catenin (E-5) and HA were acquired from Santa Cruz Biotechnology (Santa Cruz, CA). Polyclonal phospho-β-catenin (Ser33/Ser37)-specific antibody, mouse monoclonal antibodies for FLAG and tubulin, and EGF were purchased from Sigma, along with Hygromycin, AKT inhibitor IV, active His-tagged AKT1 (purified from insect cells), and protein kinase A (purified from bovine heart) from EMD Biosciences. Active GST-AKT2 (purified from insect cells) was obtained from Biomol International (Plymouth Meeting, PA), Hoechst 33342, fluorescein isothiocyanate-conjugated anti-mouse antibody and Texas Red-conjugated anti-rabbit antibody were from Molecular Probes (Eugene, OR), and HyFect transfection reagents was from Denville Scientific (Metuchen, NJ). GelCode Blue Stain Reagent was obtained from Pierce. Transfection—Cells were plated at a density of 4 × 105/60-mm-diameter dish 18 h prior to transfection. Transfection was performed using or HyFect reagents to the cultures were with for at that were and for under and of proteins with a modified from cells was by and with as Z. D. A. W. M. Cell. Biol. 1998; PubMed Scopus Google Scholar). and human β-catenin was into and or into and or and or were made using the La CA). and have been Z. Y. S. H. 2002; 21: PubMed Google Scholar). of and of protein were in and as Z. S. C. Hunter T. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In invasion was by the invasion of the cells with a were with of a of in Cells were and cell 1 × was in a cells that the and the were with and using a a with were in and at In kinase were by with or without active AKT or in kinase containing of 1 and 20 for 20 at were by of and for were then by and for to the transcriptional activity of TCF/LEF-1, CHO cells were in at × h TCF/LEF-1 or were with of or of β-catenin with or without of AKT1 of or of h the medium was with serum for and EGF was h of the cell were used for activity. were and with primary and Hoechst 33342, to Cells were using a with a from was used to GelCode was with of modified at for were by with a of a and a a × was performed CA). A of the was and by of MA). were identified by of the the for Biotechnology protein using and CA). of and and of cells were using the nuclear from Active and the from cells with or of β-catenin for were in the absence of for 20 for 1 h with and in medium containing for or were with were then and to for to AKT β-Catenin at Ser552 in and in that EGF in of β-catenin into the nucleus and increased transcriptional activity without altering its stability and phosphorylation level by GSK-3β (16Lu Z. Ghosh S. Wang Z. Hunter T. Cancer Cell. 2003; 4: 499-515Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar). the increased transcriptional activity of β-catenin is to a we a of β-catenin from cells with candidate was detected by of Ser552 was then identified as a phosphorylation in this β-catenin peptide by of at the of the peptide is to the of the in of β-catenin is to the AKT phosphorylation motif F.B. M. B.A. P. 1996; PubMed Scopus Google and the phosphorylation M. 1996; PubMed Scopus Google Scholar). this was also as AKT or phosphorylation by using the the β-catenin at Ser552, we performed in vitro kinase with active or with or in which the phosphorylation was to S. N. Y. D. J. Biol. 281: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. Kikuchi A. Cell. Biol. PubMed Scopus Google Scholar). and with S. N. Y. D. J. Biol. 281: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. Kikuchi A. Cell. Biol. PubMed Scopus Google phosphorylated β-catenin, and this phosphorylation was by at but not at Ser552 In both active AKT1 and active were to β-catenin, and with AKT inhibitor F. S. C.L. J. Cancer Cell. 2003; 4: Full Text Full Text PDF PubMed Scopus Google or at Ser552 but not at phosphorylated β-catenin and β-catenin but not β-catenin detected by a antibody recognizing phosphorylated RRX(S/T) indicating that this antibody phosphorylated β-catenin at Ser552. antibody not not that AKT, but not PKA, phosphorylates β-catenin at Ser552 in AKT phosphorylates β-catenin in active AKT1 was with β-catenin, β-catenin or β-catenin into 293T cells. of protein with the phospho-β-catenin Ser552 antibody that active AKT1 phosphorylation of β-catenin and β-catenin but not the β-catenin Similarly, active was of phosphorylation of β-catenin but not the β-catenin that β-catenin was phosphorylated by AKT at Ser552 but not in vivo. EGF AKT Cell. PubMed Scopus Google Scholar). the of EGF β-catenin cells were with EGF for in EGF phosphorylation of β-catenin at Ser552, which was by with AKT inhibitor is with β-catenin phosphorylation at Ser552 in response to EGF as detected by β-Catenin by AKT from Cell and into the and in and β-catenin phosphorylation by AKT its a active AKT1 or AKT1 was into cells. of AKT1 but not AKT1 in of a of β-catenin from cell-cell contacts into the cytosol and nucleus were also expression of and not a β-catenin in which was into increased and nuclear in to or of β-catenin that was in cell-cell contacts detected in and nuclear β-catenin in to its WT, whereas the nuclear accumulation of β-catenin was Moreover, the of the nuclear protein and we not E-cadherin in the nuclear indicating that the nuclear were of not with the of β-catenin and in the cytosol and β-catenin and increased β-catenin were detected in to β-catenin the of the and of β-catenin phosphorylation by GSK-3β, which leads to degradation of β-catenin, β-catenin, β-catenin and β-catenin were with phospho-β-catenin in β-catenin and β-catenin have phosphorylation by GSK-3β to β-catenin. revealed that β-catenin and β-catenin had a to β-catenin by that β-catenin phosphorylation by AKT leads to its disassociation from cell-cell contacts without altering its phosphorylation by β-Catenin by AKT with proteins function as of by binding to a wide of proteins 2002; PubMed Scopus Google Scholar). has been that 14-3-3ζ is a protein and β-catenin transactivation by AKT Li L. R. L. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). binding motif in which a or a at with to is found in many proteins H. 2000; PubMed Scopus Google and 2002; PubMed Scopus Google is to of β-catenin. the of β-catenin phosphorylated by AKT its with β-catenin was with and without a AKT1 or AKT1 into 293T cells. of 14-3-3ζ with antibody that expression of active in to its increased the interaction 14-3-3ζ and β-catenin with the activity of AKT in this the β-catenin in to was in its binding to whereas the β-catenin more 14-3-3ζ that phosphorylation of β-catenin at Ser552 by AKT increases the β-catenin and Phosphorylation of β-Catenin by AKT of β-Catenin and Cell β-catenin interacts with transcription factors of the TCF/LEF-1 family, leading to the increased expression of downstream β-Catenin phosphorylated by AKT into the the of β-catenin phosphorylation by AKT TCF/LEF-1 transcriptional the TCF/LEF-1 or a was with and without active AKT1 with β-catenin or β-catenin of active AKT1 increased TCF/LEF-1 transcriptional activity In to β-catenin, β-catenin had transcriptional in the absence or in the of active expression of β-catenin the of active AKT1 or TCF/LEF-1 transcriptional activity with the increased nuclear expression of β-catenin increased TCF/LEF-1 transcriptional in to β-catenin β-Catenin transcriptional activity has been to tumor development. the of phosphorylation of β-catenin by AKT tumor cell invasion, cells were with β-catenin, β-catenin or β-catenin and a invasion was expression of β-catenin cell invasion, in to cell expression of β-catenin, expression of β-catenin enhanced tumor cell invasion and that β-catenin phosphorylation by AKT promotes tumor cell β-Catenin, as a component of both Wnt signaling and cell-cell plays a role in cell and A. R. Cell Dev. Biol. 1998; 14: PubMed Scopus Google Scholar, R.T. C. M. J. Cell Biol. 1996; PubMed Scopus Google Scholar, J. R. V. B. Birchmeier C. Birchmeier W. J. Cell Biol. 2000; PubMed Scopus Google Scholar). β-Catenin mouse at H. L. M. L. K. Kemler R. 1995; PubMed Google Scholar). β-Catenin in that We that β-catenin and phosphorylation of β-catenin by AKT in the of β-catenin from cell-cell and in its transcriptional activity. mutations of Wnt lead to nuclear of β-catenin and are in tumor and H. 2003; PubMed Scopus Google Scholar). Wnt-independent signaling, is also in regulation of β-catenin transactivation and (26Lu Z. Hunter T. Cell Cycle. 2004; 3: 571-573Crossref PubMed Google Scholar). signaling activated by growth such as EGF, growth growth growth and (15Muller T. Bain G. Wang X. Papkoff J. Exp. Cell Res. 2002; 280: 119-133Crossref PubMed Scopus (153) Google Scholar, 16Lu Z. Ghosh S. Wang Z. Hunter T. Cancer Cell. 2003; 4: 499-515Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, C. A. F. G. Perret C. J. 2001; PubMed Scopus Google Scholar, V. R. C. L. 2001; PubMed Scopus Google Scholar). In response to stimulation, AKT phosphorylates GSK-3β at which leads to of GSK-3β and of β-catenin-TCF/LEF-1 transcriptional activity Science. 2001; PubMed Scopus Google Scholar, P. M. B.A. Nature. 1995; PubMed Scopus Google Scholar). In to this that AKT phosphorylates β-catenin both in vitro and in vivo. of Ser552 of β-catenin into or not its phosphorylation level by GSK-3β or its in to WT, indicating that phosphorylation of β-catenin at Ser552 by AKT not alter β-catenin protein phosphorylation at this β-catenin to from cell-cell contacts and accumulate in the of the AKT phosphorylation transcriptional activity of TCF/LEF-1 by AKT of AKT TCF/LEF-1 transcriptional activity is AKT up-regulation of β-catenin transcriptional activity by phosphorylation and of AKT β-catenin-TCF/LEF-1 transcriptional activity both by stabilization of β-catenin of GSK-3β and by phosphorylation of β-catenin, which enhances β-catenin nuclear In to phosphorylation of β-catenin at its by and GSK-3β H. 2003; PubMed Scopus Google Scholar, S. A. Y. J.S. E. M. Y. I. Genes Dev. 2002; 16: PubMed Scopus Google Scholar, C. Li Y. M. C. Y. Z. X. X. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Y. J.S. H. S. T. A. EMBO J. 2002; 21: PubMed Scopus Google β-catenin phosphorylated by at I. J. M. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google and at S. N. Y. D. J. Biol. 281: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. Kikuchi A. Cell. Biol. PubMed Scopus Google which β-catenin transactivation by β-catenin it was that phosphorylation of the protein the interaction and protein and enhances β-catenin degradation F. F. S. 2002; 21: PubMed Scopus Google Scholar). β-catenin at promotes the with its protein, thus β-catenin-TCF/LEF-1 transcriptional of this phosphorylation β-catenin stability were S. N. Y. D. J. Biol. 281: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. Kikuchi A. Cell. Biol. PubMed Scopus Google Scholar). Ser552 was to a phosphorylation of S. N. Y. D. J. Biol. 281: Full Text Full Text PDF PubMed Scopus Google Scholar). we not of phosphorylation of the β-catenin by with In of AKT and of Ser552 of β-catenin, but not phosphorylation phosphorylation by both AKT1 and and by antibody, this antibody also such as the motif for and Active AKT phosphorylates proteins containing the F.B. M. B.A. P. 1996; PubMed Scopus Google Scholar). that AKT is also to or in the S. M. J. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, A. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google or J.L. S. B. PubMed Scopus Google Scholar). We demonstrated that AKT phosphorylates Ser552 in the of β-catenin, that a phosphorylation by a of proteins that to a of signaling that are phosphorylated at the H. 2000; PubMed Scopus Google the of its is by the nuclear of the by C. L. J. EMBO J. PubMed Scopus Google Scholar). in with β-catenin, transactivation of β-catenin by AKT Li L. R. L. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). of β-catenin is a binding motif for β-Catenin its binding to 14-3-3ζ and has a transcriptional whereas β-catenin enhances this binding and increases its in to β-catenin. β-catenin has nuclear which that 14-3-3ζ of its binding proteins A. F. J. J. D. J. Cell Biol. 2002; PubMed Scopus Google Scholar). has been that AKT1 and have in tumor cell growth and whereas AKT1 and have or the cell types and D. M. P. N. S. J.S. J. Cell Biol. PubMed Scopus Google Scholar, C. J. Y. Cell. PubMed Scopus Google Scholar, M. I. P. S. A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, K. J. J. Biol. 281: Full Text Full Text PDF PubMed Scopus Google Scholar, V. J.R. Cell Biol. 16: Full Text Full Text PDF PubMed Scopus Google Scholar, L. C. V. C. D. B.A. A. Cell. Biol. PubMed Scopus Google Scholar). that activated of AKT1 and are to β-catenin in vitro and in vivo. expression of activated AKT1 or in the of β-catenin from cell-cell contacts and it that AKT1 and the for regulation of its β-catenin has a transcriptional activity than or β-catenin, which with of nuclear cells β-catenin enhanced invasion in to the cells or Ser552 β-catenin. of β-catenin increases the transcription of that tumor cell such as MYC (12He T.C. Sparks A.B. Rago C. Hermeking H. Zawel L. da Costa L.T. Morin P.J. Vogelstein B. Kinzler K.W. Science. 1998; 281: 1509-1512Crossref PubMed Scopus (4084) Google CCND1 (which encodes O. McCormick F. Nature. 1999; 398: 422-426Crossref PubMed Scopus (3259) Google Scholar, 14Shtutman M. Zhurinsky J. Simcha I. Albanese C. D'Amico M. Pestell R. Ben-Ze'ev A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 5522-5527Crossref PubMed Scopus (1919) Google and B. M. A. A. M. C. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google and that tumor cell invasion, such as T. A. S. F. T. Am. J. Pathol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, B. Polakis P. 1999; PubMed Scopus Google and O. J. Cancer Res. 2003; Google Scholar). is to phosphorylation of β-catenin at Ser552 a of downstream that tumor development. or has been found in many types of cancers, with of AKT by or growth factor and regulation of and and to tumor K. Biol. PubMed Scopus Google Scholar, Med. PubMed Scopus Google Scholar, J. Cell Dev. Biol. 2004; PubMed Scopus Google Scholar). phosphorylation and transactivation of β-catenin are the activity of We have that in Wnt-independent β-catenin transactivation by of whereas of the of β-catenin (16Lu Z. Ghosh S. Wang Z. Hunter T. Cancer Cell. 2003; 4: 499-515Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar). and of by EGF signaling in such as growth factor and (16Lu Z. Ghosh S. Wang Z. Hunter T. Cancer Cell. 2003; 4: 499-515Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, T. A. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google which in turn to AKT activation. AKT β-catenin of GSK-3β β-catenin, resulting in its disassociation from cell-cell contacts and nuclear β-catenin-TCF/LEF-1 transcriptional which in turn contributes to tumor cell invasion and tumor development. We for for and of and of for 14-3-3ζ and Li Cancer for CHO AA8 cells. We for and for critical of this