- Open Access
Aldolase positively regulates of the canonical Wnt signaling pathway
- Michal Caspi†1,
- Gili Perry†1,
- Nir Skalka1,
- Shilhav Meisel1,
- Anastasia Firsow1,
- Maayan Amit1 and
- Rina Rosin-Arbesfeld1Email author
© Caspi et al.; licensee BioMed Central Ltd. 2014
Received: 8 January 2014
Accepted: 20 June 2014
Published: 4 July 2014
The Wnt signaling pathway is an evolutionary conserved system, having pivotal roles during animal development. When over-activated, this signaling pathway is involved in cancer initiation and progression. The canonical Wnt pathway regulates the stability of β-catenin primarily by a destruction complex containing a number of different proteins, including Glycogen synthase kinase 3β (GSK-3β) and Axin, that promote proteasomal degradation of β-catenin. As this signaling cascade is modified by various proteins, novel screens aimed at identifying new Wnt signaling regulators were conducted in our laboratory. One of the different genes that were identified as Wnt signaling activators was Aldolase C (ALDOC). Here we report that ALDOC, Aldolase A (ALDOA) and Aldolase B (ALDOB) activate Wnt signaling in a GSK-3β-dependent mechanism, by disrupting the GSK-3β-Axin interaction and targeting Axin to the dishevelled (Dvl)-induced signalosomes that positively regulate the Wnt pathway thus placing the Aldolase proteins as novel Wnt signaling regulators.
One of the fundamental tasks of a cell in order to control its fate and the function of the entire organism is to create dynamic systems of signaling pathways. Today, it is well accepted that a few signaling pathways control the major developmental processes. When aberrantly regulated theses pathways lead to devastating diseases ranging from neurological diseases to cancer. One such pathway, which when up-regulated is implicated in a growing list of degenerative diseases and in most cases of colorectal cancer (CRC) is the Wnt signaling pathway . In un-stimulated cell, the Wnt signaling cascade is silenced due to the activity of a dedicated cytoplasmic destruction complex that phosphorylates β-catenin, the key effector of the canonical Wnt pathway, marking it for ubiquitination, and subsequent degradation. This destruction complex consists of the scaffold protein Axin, the tumor suppressor adenomatous polyposis coli (APC) and the kinases glycogen synthase kinase-3 (GSK-3) α/β and casein kinase-1α (CKIα) [2, 3]. The Wnt signaling cascade initiates with binding of the Wnt ligand to its receptor frizzled (Fz) and co-receptor low-density lipoprotein receptor-related protein 5/6 (LRP5/6). This event ultimately leads to accumulation and nuclear translocation of β-catenin resulting in expression of Wnt target genes . Still, the mechanism of the Wnt signal transmission remains incompletely understood. According to the current model, the activated Wnt receptors recruit dishevelled (Dvl) to the plasma membrane. In turn, Dvl along with other Wnt signaling regulators such as LRP induce the formation of “puncta-like” structures classified as LRP-signalosomes . In the signalosomes LRP is phosphorylated resulting in inhibition of GSK-3β which leads to the “β-catenin destruction complex” inactivation and accumulation of β-catenin. However this model is still being challenged and new Wnt signaling components and mechanisms of action are frequently being described. In an attempt to identify new Wnt signaling components we utilized a novel screening technique based on expression of an episomal cDNA library in mammalian cells followed by selection of clones that survive only in the continuous presence of Wnt stimulus . One of the genes that were isolated in three separate experiments was Aldolase C fructose bisphosphate (ALDOC) the fourth enzyme of glycolysis, which catalyzes reversible cleavage of fructose 1,6-bisphosphate into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate . In vertebrates, the Aldolase family consists of three isozymes that are structurally very similar: Aldolase A (ALDOA), the muscle and red blood cells isoform; Aldolase B (ALDOB), the liver, kidney and intestine isoform; and ALDOC, the brain and nervous system isoform [8, 9]. Although the role of Aldolase in metabolism is well established, there is growing evidence for many alternative functions for this enzyme. In particular, Aldolase interacts with various proteins unrelated to glycolytic enzymes, including cytoskeleton proteins such as F-actin [10, 11], WASP  and tubulin . Aldolase also interacts with other types of proteins such as proteins involved in vesicle and intracellular trafficking [14–16] proton pumps [16, 17] and is crucial for proliferation of cancer cells through a non-glycolytic pathway .
In the present study we show that Aldolase activates Wnt signaling by forming a complex with GSK-3β that disrupts the GSK-3β-Axin interaction leading to membrane translocation of Axin. These findings indicate that Aldolase isomers can function as novel regulators of the canonical, oncogenic Wnt signaling pathway and may become new anti-cancer therapeutic targets.
Materials and methods
Cell culture and transfection
Human embryonic kidney 293T (HEK293T), human cervical cancer (HeLa), monkey kidney (COS-7) and the human colon carcinoma SW480 cell lines were maintained in Dulbecco’s modified Eagle’s medium (GIBCO) supplemented with 10% fetal bovine serum and 100 units/ml penicillin/streptomycin (Beit-Haemek). Cells were cultured at 37°C in a humidified incubator with 5% CO2. For HEK293T cells, transfections were carried out using the standard CaPO4 precipitation method, or using Polyethylenimine (PEI) reagent (Polysciences) following manufacturer’s guidelines. For HeLa, COS-7 and SW480 cells, Polyethylenimine (PEI) reagent (Polysciences) was used. SB (SB-216763) is a small molecule that competes with ATP and potently inhibits the activity of GSK-3β was used (Sigma, Israel; 10 μM; 4 hours).
GFP-ALDOB expression vector was constructed by inserting ALDOB cDNA (provided by Marçal Pastor-Anglada, Universitat de Barcelona, Barcelona, Spain) into pEGFP-C2 (Clontech, Palo Alto, CA) using Eco RI and Sal I restriction sites. GFP-ALDOC was constructed in our laboratory by amplifying ALDOC cDNA by PCR (using the primers 5′-AGAGGGATCCGCAT GCCTCACTCGTACCCAGCC-3′ and 5′- AGAGCTCGAGGTAGGCATGGTTG GCAATGTAGAG-3′) and subcloning into pEGFP-C2 using Bgl II and Sal I restriction sites. The ORF of human Aldolase A was cloned into pEGFP-C2 vector using EcoRI and KpnI sites. For PCR we used the primers: EcoRI-AldA-Fw- AAAAGAATTCATGCCCTACCAATATCCAGC, and KpnI-AldA-Rv-AAAGGTACCATAGGCGTGGTTAGAGACGAAG. HA-GSK-3β and FLAG–GSK-3β expression vectors were kindly provided by T.C. Dale (Developmental Biology, Chester Beatty Laboratories, Institute of Cancer Research, London, UK) and Hagit Eldar-Finkelman (Tel-Aviv University, Tel-Aviv, Israel), respectively. GFP-Axin and FLAG-Axin expression vectors were kindly provided by Mariann Bienz (MRC Laboratory of Molecular Biology, Hills Road, Cambridge, UK) and T.C. Dale, respectively, and were described previously. The Wnt-responsive TCF-dependent luciferase constructs pTOPFLASH and its mutated version pFOPFLASH were kindly provided by H. Clevers (Center for Biomedical Genetics, Utrecht, Netherlands) and were described before. pSV-β-Galactosidase Control Vector and pCMV-Renilla were purchased from Promega (Madison, WI).
Luciferase reporter assay
Twenty four hours after seeding in 24-well plates at 1×105 cells per well, cells were transfected with relevant DNA plasmids, along with pGL3-OT (pTOPFLASH) or pGL3-OF (pFOPFLASH) – luciferase reporter constructs. These constructs contain the firefly luciferase open reading frame under the control of three copies of either wild-type (pTOPFLASH) or mutated TCF binding element (pFOPFLASH) . These constructs are used for assessing changes in the canonical Wnt pathway. The β-galactosidase construct (in HEK293T cells) or CMV-Renilla (in SW480 cells) were used to monitor transfection efficiency. Forty eight hours post-transfection, cells were washed with phosphate-buffered saline (PBS) and harvested on ice using Reporter Lysis Buffer (Promega). Cell lysates were centrifuged for 15 minutes at 14,000 rpm at 4°C and their luciferase activity was measured following manufacturer’s instructions. Specificity of luciferase activity was validated using the pFOPFLASH plasmid. Residues of supernatants were analyzed by Western blotting as described below.
Western blot analysis and immunoprecipitation
HEK293T cells were transfected as indicated above, and 48 hours later washed with PBS and harvested on ice using lysis buffer (50 mM Tris pH 7.5, 150 mM NaCl, 1% Triton), or radioimmunoprecipitation assay (RIPA) buffer (50 mM Tris-HCl pH 7.4, 1% NP-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA) supplemented with 1% protease inhibitor cocktail (Sigma). Cell lysates were centrifuged for 15 minutes at 10,000-14,000 rpm at 4°C. Supernatants were separated on 7.5% or 10% SDS-polyacrylamide gel electrophoresis (SDS-PAGE), and proteins were transferred to nitrocellulose membranes. After blocking with 5% low fat milk, membranes were incubated with primary antibodies, washed three times with 0.001% tween-20 in PBS, incubated for 60 minutes with secondary antibodies, washed again three times and exposed to enhanced chemiluminescence (ECL) detection analysis using horseradish peroxidase-conjugated secondary antibodies.
For immunoprecipitation (IP) assays, cell lysates were incubated following centrifugation with anti-FLAG M2-agarose affinity gel (Sigma), with rotation for two hours at 4°C. Alternatively, cell lysates were incubated with the specific antibody for two hours on ice prior to two hours rotated incubation with protein A/G agarose (Santa Cruz Biotechnology) at 4°C. Following incubation, beads were collected by slow centrifugation, washed four times with lysis buffer and analyzed by Western blotting as described. For endogenic IP assays, mouse brain extracts were homogenized in RIPA buffer supplemented with 1% protease inhibitor cocktail. Following centrifugation, supernatants were incubated for two hours on ice with the relevant antibody or with control unimmuned serum, and then incubated at 4°C with rotation with protein A/G agarose and separated by SDS-PAGE as designated before. The following antibodies were used (for immunoblotting, unless mentioned otherwise): goat anti-Aldolase B (1:500; Santa Cruz Biotechnology), goat anti-Aldolase C (1:500; Santa Cruz Biotechnology), goat anti-Axin (1:250 for IP; Santa Cruz Biotechnology), rabbit anti-SOX-9 (1:500; Millipore) rabbit anti-GFP (1:1000; Santa Cruz Biotechnology), mouse anti-GFP (1:1000; Abcam), mouse anti-GSK-3β (1:5000; BD Transduction Laboratories), rat anti-HA (1:5000; Roche), mouse anti-FLAG (1:5000; Sigma), mouse anti-β-catenin (1:100; BD Transduction Laboratories), mouse anti-β-catenin active (1:1000; Millipore), rabbit anti-phospho-β-catenin (1:1000; cell signaling), and mouse anti-Tubulin (1:10,000; Sigma), anti-Striatin (1:1000; BD Transduction Laboratories), Rabbit anti-GSK-3β used for IP was kindly provided by Hagit Eldar-Finkelman (Tel-Aviv University, Tel-Aviv, Israel). Anti-goat horseradish peroxidase-conjugated secondary antibody was obtained from Santa Cruz Biotechnology and was used at a 1:5000 dilution. Anti-mouse and anti-rabbit secondary antibodies were obtained from Jackson Immuno Research and were used at a 1:10,000 dilution.
HEK293T, HeLa or COS-7 cells were seeded on glass coverslips in 24-well plates and transfected as mentioned previously. Forty eight hours after transfection, cells were washed with PBS and fixed in PBS containing 4% paraformaldehyde (PFA) for 20 minutes. Fixed cells were washed twice with PBS, permeabilized with PBS containing 0.1% Triton (PBT) for 10 minutes and blocked in PBS containing 1% BSA and 0.1% Triton (BBT) for one hour. Afterwards, cells were incubated at room temperature with primary antibodies for 60 minutes, washed three times with PBT, incubated with secondary antibodies for 30 minutes, and washed again three times. Finally, cell nuclei were stained with 10 μg/ml 4′,6-Diamidino-2-phenylindole (DAPI, Sigma) for 5 minutes. Slides were visualized by confocal microscopy or by phase contrast microscopy (Leica SP2, Leica Microsystems, Bannockburn, IL).
The following antibodies were used: goat anti-Aldolase B (1:100; Santa Cruz Biotechnology), goat anti-Aldolase C (1:100; Santa Cruz Biotechnology), rabbit anti-FLAG (1:400; Sigma), mouse anti-GSK-3β (1:300; BD Transduction Laboratories), rat anti-HA (1:300; Roche), mouse anti-myc (1:200; Santa Cruz Biotechnology). Anti-goat, anti-mouse, anti-rabbit and anti-rat fluorescent antibodies were obtained from Invitrogen and were used at a 1:500 dilution.
HEK293T cells were transfected with 30nM GSK siRNA (siGENOME SMART pool M-003010-03-0005 hGSK3b NM-002093), 50 or 100nM siGENOME ALDOC siRNA; NM_005165; M-012697-01-0005 or non-targeting RNA oligonucleotides as scrRNA, using DharmaFECT-1 as transfection reagent; siRNA and scrRNA oligonucleotides, together with the mentioned reagent, were all purchased from Thermo Scientific Dharmacon (Essex, UK). Cells were either harvested for western blot analysis after 72 h or transfected with the relevant DNA plasmids after 24 h. Forty eight h later the transfectedcells were harvested and analyzed using Western blots as described above All animal work was conducted according to national and international guidelines and approved by the Tel Aviv University review board.
Aldolase isomers activate the canonical Wnt signaling pathway
Aldolase activation of the Wnt pathway depends on an intact “β-catenin degradation complex”
GSK-3β interacts with Aldolase proteins
Aldolase depends on GSK-3β for activating the Wnt pathway but does not affect the phosphorylation of β-catenin
Aldolase activates Wnt signaling by disrupting the Axin-GSK-3β interaction and targeting Axin to the Dvl “puncta”
The Wnt signaling pathway is modified by various proteins, some are known and others are yet to be revealed. The presented work introduces the role of ALDOB and ALDOC as positive regulators of the pathway characterizes their relationship with components of the Wnt cascade and proposes a mechanism for their action. As over-expression of Aldolase induces Wnt signaling, Aldolase might act as a colorectal oncogene, and therefore serve as a putative therapeutic target for cancer treatment or diagnosis.
This study was supported by the Rising Tide Foundation for Clinical Cancer Research and the Gateway for Cancer Research Foundation.
- Barker N, Clevers H: Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov. 2006, 5: 997-1014. 10.1038/nrd2154 10.1038/nrd2154View ArticlePubMedGoogle Scholar
- Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P: Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996, 272: 1023-1026. 10.1126/science.272.5264.1023View ArticlePubMedGoogle Scholar
- Kimelman D, Xu W: beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene. 2006, 25: 7482-7491. 10.1038/sj.onc.1210055View ArticlePubMedGoogle Scholar
- Angers S, Moon RT: Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009, 10: 468-477.View ArticlePubMedGoogle Scholar
- Bilic J, Huang YL, Davidson G, Zimmermann T, Cruciat CM, Bienz M, Niehrs C: Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science. 2007, 316: 1619-1622. 10.1126/science.1137065View ArticlePubMedGoogle Scholar
- Skalka N, Caspi M, Caspi E, Loh YP, Rosin Arbesfeld R, Carboxypeptidase E: a negative regulator of the canonical Wnt signaling pathway. Oncogene. 2012, 32: 2836-2847.PubMed CentralView ArticlePubMedGoogle Scholar
- Buono P, Mancini FP, Izzo P, Salvatore F: Characterization of the transcription-initiation site and of the promoter region within the 5′ flanking region of the human aldolase C gene. Eur J Bioche / FEBS. 1990, 192: 805-811. 10.1111/j.1432-1033.1990.tb19294.x.View ArticleGoogle Scholar
- Arakaki TL, Pezza JA, Cronin MA, Hopkins CE, Zimmer DB, Tolan DR, Allen KN: Structure of human brain fructose 1, 6-(bis)phosphate aldolase: linking isozyme structure with function. Protein Sci Publ Protein Soc. 2004, 13: 3077-3084.View ArticleGoogle Scholar
- Tolan DR, Niclas J, Bruce BD, Lebo RV: Evolutionary implications of the human aldolase-A, -B, -C, and -pseudogene chromosome locations. Am J Hum Genet. 1987, 41: 907-924.PubMed CentralPubMedGoogle Scholar
- Arnold H, Pette D: Binding of aldolase and triosephosphate dehydrogenase to F-actin and modification of catalytic properties of aldolase. Eur J Biochem / FEBS. 1970, 15: 360-366. 10.1111/j.1432-1033.1970.tb01016.x.View ArticleGoogle Scholar
- Wang J, Morris AJ, Tolan DR, Pagliaro L: The molecular nature of the F-actin binding activity of aldolase revealed with site-directed mutants. J Biol Chem. 1996, 271: 6861-6865. 10.1074/jbc.271.12.6861View ArticlePubMedGoogle Scholar
- Buscaglia CA, Penesetti D, Tao M, Nussenzweig V: Characterization of an aldolase-binding site in the Wiskott-Aldrich syndrome protein. J Biol Chem. 2006, 281: 1324-1331. 10.1074/jbc.M506346200View ArticlePubMedGoogle Scholar
- Volker KW, Knull H: A glycolytic enzyme binding domain on tubulin. Arch Biochem Biophys. 1997, 338: 237-243. 10.1006/abbi.1996.9819View ArticlePubMedGoogle Scholar
- Rangarajan ES, Park H, Fortin E, Sygusch J, Izard T: Mechanism of aldolase control of sorting nexin 9 function in endocytosis. J Biol Chem. 2010, 285: 11983-11990. 10.1074/jbc.M109.092049PubMed CentralView ArticlePubMedGoogle Scholar
- Merkulova M, Hurtado-Lorenzo A, Hosokawa H, Zhuang Z, Brown D, Ausiello DA, Marshansky V: Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution. Am J Physiol Cell Physiol. 2011, 300: C1442-C1455. 10.1152/ajpcell.00076.2010PubMed CentralView ArticlePubMedGoogle Scholar
- Lu M, Ammar D, Ives H, Albrecht F, Gluck SL: Physical interaction between aldolase and vacuolar H + -ATPase is essential for the assembly and activity of the proton pump. J Biol Chem. 2007, 282: 24495-24503. 10.1074/jbc.M702598200View ArticlePubMedGoogle Scholar
- Lu M, Sautin YY, Holliday LS, Gluck SL: The glycolytic enzyme aldolase mediates assembly, expression, and activity of vacuolar H + -ATPase. J Biol Chem. 2004, 279: 8732-8739. 10.1074/jbc.M303871200View ArticlePubMedGoogle Scholar
- Lew CR, Tolan DR: Targeting of several glycolytic enzymes using RNA interference reveals aldolase affects cancer cell proliferation through a non-glycolytic mechanism. J Biol Chem. 2012, 287: 42554-42563. 10.1074/jbc.M112.405969PubMed CentralView ArticleGoogle Scholar
- Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW: Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997, 275: 1787-1790. 10.1126/science.275.5307.1787View ArticlePubMedGoogle Scholar
- Kusakabe T, Motoki K, Hori K: Human aldolase C: characterization of the recombinant enzyme expressed in Escherichia coli. J Biochem. 1994, 115: 1172-1177.PubMedGoogle Scholar
- Sakakibara M, Takahashi I, Takasaki Y, Mukai T, Hori K: Construction and expression of human aldolase A and B expression plasmids in Escherichia coli host. Biochim Biophys Acta. 1989, 1007: 334-342. 10.1016/0167-4781(89)90156-5View ArticlePubMedGoogle Scholar
- Rowan AJ, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A, Bicknell D, Bodmer WF, Tomlinson IPM: APC mutations in sporadic colorectal tumors: A mutational “hotspot” and interdependence of the “two hits”. Proc Natl Acad Sci U S A. 2000, 97: 3352-3357. 10.1073/pnas.97.7.3352PubMed CentralView ArticlePubMedGoogle Scholar
- Rylatt DB, Aitken A, Bilham T, Condon GD, Embi N, Cohen P: Glycogen synthase from rabbit skeletal muscle. Amino acid sequence at the sites phosphorylated by glycogen synthase kinase-3, and extension of the N-terminal sequence containing the site phosphorylated by phosphorylase kinase. Eur J Biochem / FEBS. 1980, 107: 529-537.View ArticleGoogle Scholar
- Davies SP, Reddy H, Caivano M, Cohen P: Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000, 351: 95-105. 10.1042/0264-6021:3510095PubMed CentralView ArticlePubMedGoogle Scholar
- Cliffe A, Hamada F, Bienz M: A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling. Curr Biol CB. 2003, 13: 960-966. 10.1016/S0960-9822(03)00370-1.View ArticlePubMedGoogle Scholar
- Nusse R, Varmus H: Three decades of Wnts: a personal perspective on how a scientific field developed. EMBO J. 2012, 31: 2670-2684. 10.1038/emboj.2012.146PubMed CentralView ArticlePubMedGoogle Scholar
- Li VS, Ng SS, Boersema PJ, Low TY, Karthaus WR, Gerlach JP, Mohammed S, Heck AJ, Maurice MM, Mahmoudi T, Clevers H: Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell. 2012, 149: 1245-1256. 10.1016/j.cell.2012.05.002View ArticlePubMedGoogle Scholar
- Warburg O, Wind F, Negelein E: The Metabolism of Tumors in the Body. J Gene Physiol. 1927, 8: 519-530. 10.1085/jgp.8.6.519.View ArticleGoogle Scholar
- Mhawech-Fauceglia P, Wang D, Kesterson J, Beck A, de Mesy Bentley KL, Shroff S, Syriac S, Frederick P, Liu S, Odunsi K: Aldolase mRNA expression in endometrial cancer and the role of clotrimazole in endometrial cancer cell viability and morphology. Histopathology. 2011, 59: 1015-1018. 10.1111/j.1365-2559.2011.03944.xView ArticlePubMedGoogle Scholar
- Ojika T, Imaizumi M, Abe T, Kato K: Immunochemical and immunohistochemical studies on three aldolase isozymes in human lung cancer. Cancer. 1991, 67: 2153-2158. 10.1002/1097-0142(19910415)67:8<2153::AID-CNCR2820670825>3.0.CO;2-ZView ArticlePubMedGoogle Scholar
- Peng Y, Li X, Wu M, Yang J, Liu M, Zhang W, Xiang B, Wang X, Li X, Li G, Shen S: New prognosis biomarkers identified by dynamic proteomic analysis of colorectal cancer. Mol BioSyst. 2012, 8: 3077-3088. 10.1039/c2mb25286dView ArticlePubMedGoogle Scholar
- Peng SY, Lai PL, Pan HW, Hsiao LP, Hsu HC: Aberrant expression of the glycolytic enzymes aldolase B and type II hexokinase in hepatocellular carcinoma are predictive markers for advanced stage, early recurrence and poor prognosis. Oncol Rep. 2008, 19: 1045-1053.PubMedGoogle Scholar
- Asaka M, Kimura T, Nishikawa S, Miyazuki T, Alpert E: Decreased serum aldolase B levels in patients with malignant tumors. Cancer. 1988, 62: 2554-2557. 10.1002/1097-0142(19881215)62:12<2554::AID-CNCR2820621217>3.0.CO;2-XView ArticlePubMedGoogle Scholar
- Schwarz-Romond T, Merrifield C, Nichols BJ, Bienz M: The Wnt signalling effector Dishevelled forms dynamic protein assemblies rather than stable associations with cytoplasmic vesicles. J Cell Sci. 2005, 118: 5269-5277. 10.1242/jcs.02646View ArticlePubMedGoogle Scholar
- Levina E, Oren M, Ben-Ze’ev A: Downregulation of beta-catenin by p53 involves changes in the rate of beta-catenin phosphorylation and Axin dynamics. Oncogene. 2004, 23: 4444-4453. 10.1038/sj.onc.1207587View ArticlePubMedGoogle Scholar
- Hart MJ, De Los Santos R, Albert IN, Rubinfeld B, Polakis P: Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol CB. 1998, 8: 573-581. 10.1016/S0960-9822(98)70226-X.View ArticlePubMedGoogle Scholar
- Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S, Kikuchi A: Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J Biol Chem. 1999, 274: 10681-10684. 10.1074/jbc.274.16.10681View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.