The beta-catenin destruction complex plays a key role in the canonical Wnt signaling pathway. In the absence of Wnt signaling, this complex controls the levels of cytoplamic beta-catenin. Beta-catenin associates with and is phosphorylated by the destruction complex. Phosphorylated beta-catenin is recognized and ubiquitinated by the SCF-beta TrCP ubiquitin ligase complex and is subsequently degraded by the proteasome (reviewed in Kimelman and Xu, 2006).
View original pathway at:Reactome.
Freemantle SJ, Portland HB, Ewings K, Dmitrovsky F, DiPetrillo K, Spinella MJ, Dmitrovsky E.; ''Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMedEurope PMCScholia
Tran H, Hamada F, Schwarz-Romond T, Bienz M.; ''Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains.''; PubMedEurope PMCScholia
Willert K, Shibamoto S, Nusse R.; ''Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex.''; PubMedEurope PMCScholia
Brantjes H, Barker N, van Es J, Clevers H.; ''TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling.''; PubMedEurope PMCScholia
Muhr J, Andersson E, Persson M, Jessell TM, Ericson J.; ''Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral neural tube.''; PubMedEurope PMCScholia
Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E.; ''The way Wnt works: components and mechanism.''; PubMedEurope PMCScholia
Chen G, Nguyen PH, Courey AJ.; ''A role for Groucho tetramerization in transcriptional repression.''; PubMedEurope PMCScholia
Dajani R, Fraser E, Roe SM, Yeo M, Good VM, Thompson V, Dale TC, Pearl LH.; ''Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex.''; PubMedEurope PMCScholia
Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y.; ''Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors.''; PubMedEurope PMCScholia
Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A.; ''Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin.''; PubMedEurope PMCScholia
Luo W, Peterson A, Garcia BA, Coombs G, Kofahl B, Heinrich R, Shabanowitz J, Hunt DF, Yost HJ, Virshup DM.; ''Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex.''; PubMedEurope PMCScholia
Jho E, Lomvardas S, Costantini F.; ''A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression.''; PubMedEurope PMCScholia
Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I.; ''Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway.''; PubMedEurope PMCScholia
Miyasaka H, Choudhury BK, Hou EW, Li SS.; ''Molecular cloning and expression of mouse and human cDNA encoding AES and ESG proteins with strong similarity to Drosophila enhancer of split groucho protein.''; PubMedEurope PMCScholia
Salahshor S, Woodgett JR.; ''The links between axin and carcinogenesis.''; PubMedEurope PMCScholia
Choi CY, Kim YH, Kwon HJ, Kim Y.; ''The homeodomain protein NK-3 recruits Groucho and a histone deacetylase complex to repress transcription.''; PubMedEurope PMCScholia
Arce L, Pate KT, Waterman ML.; ''Groucho binds two conserved regions of LEF-1 for HDAC-dependent repression.''; PubMedEurope PMCScholia
Song H, Hasson P, Paroush Z, Courey AJ.; ''Groucho oligomerization is required for repression in vivo.''; PubMedEurope PMCScholia
Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP.; ''Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase.''; PubMedEurope PMCScholia
Tran H, Polakis P.; ''Reversible modification of adenomatous polyposis coli (APC) with K63-linked polyubiquitin regulates the assembly and activity of the β-catenin destruction complex.''; PubMedEurope PMCScholia
Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X.; ''Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.''; PubMedEurope PMCScholia
Liu J, Xing Y, Hinds TR, Zheng J, Xu W.; ''The third 20 amino acid repeat is the tightest binding site of APC for beta-catenin.''; PubMedEurope PMCScholia
Roose J, Molenaar M, Peterson J, Hurenkamp J, Brantjes H, Moerer P, van de Wetering M, Destrée O, Clevers H.; ''The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors.''; PubMedEurope PMCScholia
Winkler CJ, Ponce A, Courey AJ.; ''Groucho-mediated repression may result from a histone deacetylase-dependent increase in nucleosome density.''; PubMedEurope PMCScholia
Latres E, Chiaur DS, Pagano M.; ''The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin.''; PubMedEurope PMCScholia
Kimelman D, Xu W.; ''beta-catenin destruction complex: insights and questions from a structural perspective.''; PubMedEurope PMCScholia
Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, Kim JC, Feinberg AP, Gerald WL, Vargas SO, Chin L, Iafrate AJ, Bell DW, Haber DA.; ''An X chromosome gene, WTX, is commonly inactivated in Wilms tumor.''; PubMedEurope PMCScholia
Kim SE, Huang H, Zhao M, Zhang X, Zhang A, Semonov MV, MacDonald BT, Zhang X, Garcia Abreu J, Peng L, He X.; ''Wnt stabilization of β-catenin reveals principles for morphogen receptor-scaffold assemblies.''; PubMedEurope PMCScholia
Su Y, Fu C, Ishikawa S, Stella A, Kojima M, Shitoh K, Schreiber EM, Day BW, Liu B.; ''APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase.''; PubMedEurope PMCScholia
Cinnamon E, Paroush Z.; ''Context-dependent regulation of Groucho/TLE-mediated repression.''; PubMedEurope PMCScholia
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMedEurope PMCScholia
Tang W, Dodge M, Gundapaneni D, Michnoff C, Roth M, Lum L.; ''A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer.''; PubMedEurope PMCScholia
Swingler TE, Bess KL, Yao J, Stifani S, Jayaraman PS.; ''The proline-rich homeodomain protein recruits members of the Groucho/Transducin-like enhancer of split protein family to co-repress transcription in hematopoietic cells.''; PubMedEurope PMCScholia
Brantjes H, Roose J, van De Wetering M, Clevers H.; ''All Tcf HMG box transcription factors interact with Groucho-related co-repressors.''; PubMedEurope PMCScholia
Seeling JM, Miller JR, Gil R, Moon RT, White R, Virshup DM.; ''Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A.''; PubMedEurope PMCScholia
Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW.; ''The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro.''; PubMedEurope PMCScholia
Calviello G, Resci F, Serini S, Piccioni E, Toesca A, Boninsegna A, Monego G, Ranelletti FO, Palozza P.; ''Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2.''; PubMedEurope PMCScholia
Hamada F, Bienz M.; ''The APC tumor suppressor binds to C-terminal binding protein to divert nuclear beta-catenin from TCF.''; PubMedEurope PMCScholia
Xing Y, Clements WK, Le Trong I, Hinds TR, Stenkamp R, Kimelman D, Xu W.; ''Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function.''; PubMedEurope PMCScholia
Ren B, Chee KJ, Kim TH, Maniatis T.; ''PRDI-BF1/Blimp-1 repression is mediated by corepressors of the Groucho family of proteins.''; PubMedEurope PMCScholia
Saitoh T, Moriwaki J, Koike J, Takagi A, Miwa T, Shiokawa K, Katoh M.; ''Molecular cloning and characterization of FRAT2, encoding a positive regulator of the WNT signaling pathway.''; PubMedEurope PMCScholia
Brannon M, Brown JD, Bates R, Kimelman D, Moon RT.; ''XCtBP is a XTcf-3 co-repressor with roles throughout Xenopus development.''; PubMedEurope PMCScholia
Daniels DL, Weis WI.; ''Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation.''; PubMedEurope PMCScholia
Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, Lee JJ, Tilghman SM, Gumbiner BM, Costantini F.; ''The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation.''; PubMedEurope PMCScholia
Hanaki H, Yamamoto H, Sakane H, Matsumoto S, Ohdan H, Sato A, Kikuchi A.; ''An anti-Wnt5a antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis.''; PubMedEurope PMCScholia
Tauriello DV, Haegebarth A, Kuper I, Edelmann MJ, Henraat M, Canninga-van Dijk MR, Kessler BM, Clevers H, Maurice MM.; ''Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Kim MJ, Chia IV, Costantini F.; ''SUMOylation target sites at the C terminus protect Axin from ubiquitination and confer protein stability.''; PubMedEurope PMCScholia
Chen G, Courey AJ.; ''Groucho/TLE family proteins and transcriptional repression.''; PubMedEurope PMCScholia
Pinto M, Lobe CG.; ''Products of the grg (Groucho-related gene) family can dimerize through the amino-terminal Q domain.''; PubMedEurope PMCScholia
Valenta T, Lukas J, Korinek V.; ''HMG box transcription factor TCF-4's interaction with CtBP1 controls the expression of the Wnt target Axin2/Conductin in human embryonic kidney cells.''; PubMedEurope PMCScholia
Duval A, Rolland S, Tubacher E, Bui H, Thomas G, Hamelin R.; ''The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines.''; PubMedEurope PMCScholia
Cuilliere-Dartigues P, El-Bchiri J, Krimi A, Buhard O, Fontanges P, Fléjou JF, Hamelin R, Duval A.; ''TCF-4 isoforms absent in TCF-4 mutated MSI-H colorectal cancer cells colocalize with nuclear CtBP and repress TCF-4-mediated transcription.''; PubMedEurope PMCScholia
Chen G, Fernandez J, Mische S, Courey AJ.; ''A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development.''; PubMedEurope PMCScholia
B-TrCP associates with phosphorylated beta-catenin through the B-TrCP WD40 repeat region. Currently, it is unclear whether the ubiquitin ligase binds beta-catenin after it leaves the complex. It is equally possible that it binds beta-catenin while beta-catenin is still bound to Axin.
The exact composition of the destruction complex is not known. A number of components appear to form a core complex, while others may associate with the complex transiently when a Wnt signal is present (reviewed in Kimelman and Xu, 2006). The core components include Axin, glycogen synthase kinase 3 (GSK-3), Casein kinase 1 (CKI) alpha, beta-catenin, Protein phosphatase 2A (PP2A) and Adenomatous Polyposis Coli (APC). CK1 epsilon, Diversin and PP1 may also be components of the complex.
APC is phosphorylated on the 20 aa repeats by CK1 and potentially GSK-3. This significantly increases the binding affinity of the APC 20 aa repeats for beta-catenin, causing one of them to bind b-catenin in the same region as beta-catenin binds Axin, thus displacing beta-catenin from Axin ( Step 5 above) (Reviewed in Kimelman, 2006).
The phosphorylation of the 20 aa repeats in APC results in an increase in affinity for beta-catenin (Ha et al., 2004, Xing et al., 2004; Liu et al., 2006). The binding site of phospho -(20 aa) APC on beta-catenin overlaps the binding site of Axin on beta catenin. In addition, phosphorylated APC prevents the association of Axin with beta-catenin (Ha et al., 2004, Xing et al., 2004). In this model, phosphorylated APC may compete with Axin for beta-catenin binding, resulting in dissociation of the Axin:beta-catenin interaction in the destruction complex (see Kimelman and Xu 2006).
Beta-catenin is then phosphorylated at Ser33. Phosphorylated S37 and S33 together with neighboring residues constitute the recognition motif for beta-TrCP.
Beta-catenin associates with the destruction complex through an interaction with Axin and or APC. This association may also involve interactions with the 15 aa repeats in APC (Spink et al., 2001) or the third APC 20aa repeat and its N-terminal flanking residues (Ha et al., 2004, Xing et al., 2004; Liu et al., 2006).
CK1a binds to Axin and phosphorylates beta-catenin at Ser45 priming GSK3 mediated phosphorylation at the more N-terminal residues (Amit et al., 2002; Liu et al., 2002; Yanagawa et al., 2002).
B-TrCP associates with phosphorylated beta-catenin through the B-TrCP WD40 repeat region. Currently, it is unclear whether the ubiquitin ligase binds beta-catenin after it leaves the complex. It is equally possible that it binds beta-catenin while beta-catenin is still bound to Axin.
TCF1, LEF1, TCF3 and TCF4 are HMG box-containing DNA-binding proteins that recognize WNT-responsive elements (WREs) in the promoters of WNT target genes (reviewed in Brantjes et al, 2002). In the absence of a WNT signal, promoter-bound TCF/LEF is bound by one of four Groucho homologues, TLE1, 2, 3 or 4 (Levanon et al, 1998; Brantjes et al, 2001; Daniels and Weis, 2005). Groucho/TLE proteins are co-repressors for a variety of DNA-binding transcription factors and mediate repression at least in part through their interaction with histone deacetylases such as RPD3/HDAC1 (Arce et al, 2009; Brantjes et al, 2001; Chen et al, 1999; reviewed in Chen and Courey, 2000). Groucho proteins have been shown to homo-tetramerize through a glutamine rich Q domain at the N-terminus, and this oligomerization is required for repression. The Q domain is also sufficient for interaction with TCF/LEF proteins (Brantjes et al, 2001; Chen et al, 1998; Pinto and Lobe, 1996; Song et al, 2004). Studies with purified proteins have shown that human TLE1 and 2 bind to an amino-terminal truncated form of LEF1(69-397) with an affinity comparable to that for full length LEF1 (Daniels and Weis, 2005).
Groucho/TLE mediates repression of WNT target genes in part by recruiting a histone deacetlyase to the promoter. The weakly conserved central GP domain of Groucho/TLE has been shown to interact with the histone deacetylase RPD3/HDAC1 (Brantjes et al, 2001; Chen et al, 1999). Knockdown of rpd3 in Drosophila cells, or treatment of human or Drosophila cells with the histone deacetylase inhibitor Trichostatin A significantly decreases repression of a Groucho/TLE dependent reporter gene, and Groucho and RPD3 have been shown to co-localize to chromatin of target genes by ChIP leading to deacetylation of H3K9, H3K14, K4K5, H4K8 and H4K12 (Chen et al, 1999; Choi et al 1999; Winkler et al, 2010).
AES is a naturally occuring truncated form of TLE that contains only the Q and GP domain. AES has been shown to have a dominant negative effect on TLE-mediated repression (Miyasaka et al, 1993; Roose et al, 1998; Ren et al, 1999; Swingler et al, 2004). AES is believed to form oligomers with full length TLE proteins mediated by the Q domains; because AES is unable to interact with HDAC1, these oligomers are thought to be non-functional (Muhr et al, 2001; Brantjes et al, 2001).
In the absence of WNT signal, AXIN is a phosphoprotein; candidate kinases include both GSK3beta and CK1 (Ikeda et al, 1998; Willert et al, 1999; Jho et al, 1999; Yamamoto et al, 1999; Luo et al, 2007). Phosphorylation of AXIN is thought to increase its binding affinity for beta-catenin and GSK3beta, stabilizing the destruction complex and promoting efficient degradation of beta-catenin (Willert et al, 1999; Jho et al, 1999; Luo et al, 2007). A more recent model suggests that AXIN phosphorylation may disrupt an intramolecular interaction between its DIX domain and the beta-catenin binding region, which would otherwise keep AXIN in a 'closed' inactive state (Kim et al, 2013). Activation of the WNT pathway upon ligand binding favours dephosphorylation of AXIN by inactivating the kinases and allowing the steady state dephosphorylation by candidate phosphatases PP2A and PP1 to predominate (Willert et al, 1999; Luo et al, 2007; reviewed in Saito-Diaz et al, 2013).
Transcription of WNT genes is repressed in the absence of WNT signal by TLE:HDAC complexes (reviewed in Cinnamon and Paroush, 2008; Saito-Diaz et al, 2013). Represssion may also be mediated by CTBP proteins binding to TCF7L1 and TCF7L3 (Duval et al, 2000; Cuilliere-Dartigues et al, 2006; Tang et al, 2008).
In unstimulated cells, APC is K63 polyubiquitinated in a manner that depends on its association with AXIN. Although the precise timing of APC polyubiquitination is unclear, it is disrupted by abrogation of GSK3 kinase activity and in the presence of phosphodegron mutants of beta-catenin, suggesting that the formation of a functional destruction complex is required. Destruction complex formation is also dependent upon AXIN levels, which may be regulated at least in part by the balance of its ubiquitination and sumoylation (Kim et al, 2008). Upon WNT3A stimulation, APC K63 polyubiquitination is lost coincident with disruption of the APC-AXIN interaction (Tran and Polakis, 2012). Interestingly, another study has shown that DVL is K63 polyubiquitinated upon WNT signaling (Tauriello et al, 2010), suggesting a possible model in which WNT signaling promotes a change in AXIN-K63 polyubiquitin binding partner to destabilize the destruction complex and promote pathway activation. Alternately, APC K63 polyubiquitination may protect beta-catenin from PP2A-mediated dephosphorylation and thus favour its degradation (Su et al, 2008).
AXIN1 was first identified as the product of the mouse gene fused and has since been shown to have a key role in the degradation of beta-catenin by the destruction complex (Zeng et al, 1997; reviewed in Saito-Diaz et al, 2013). Deletion, missense and nonsense mutations that lead to activated WNT signaling have been identified in the AXIN1 gene in human cancers, making AXIN1 a tumor suppressor gene (reviewed in Salahshor and Woodgett, 2005).
AMER1 was identified as a gene mutated in a subset of Wilms tumors (Rivera et al, 2007) and the protein has been shown to be a component of the beta-catenin destruction complex (Major et al, 2007).
In addition to repressing WNT-dependent targets through Groucho/TLE proteins, some TCF/LEF transcription factors may also work by recruiting the CTBP1 and CTBP2 repressors (Duval et al, 2000). CTBP-binding regions are present in the 'E-form' splice variants of TCF7L2 and in TCF7L1 and in vitro interactions have been demonstrated in Xenopus and mammals, although the in vivo relevance of these interactions is unclear (Brannon et al, 1999; Valenta et al, 2003; Cuilliere-Dartigues et al, 2006; Tang et al, 2008; Hamada and Bienz, 2004). Abrogation of the interaction interface results in a loss of TCF-CTBP colocalization and increased expression of a TCF-dependent reporter gene (Cuilliere-Dartigues et al, 2006; Tang et al, 2008).
In the absence of a WNT signal, promoter-bound TCF/LEF is bound by one of four Groucho homologues, TLE1, 2, 3 or 4 (Levanon et al, 1998; Brantjes et al, 2001; Daniels and Weis, 2005). Groucho/TLE proteins are co-repressors for a variety of DNA-binding transcription factors and mediate repression at least in part through their interaction with histone deacetylases such as RPD3/HDAC1 (Arce et al, 2009; Brantjes et al, 2001; Chen et al, 1999; reviewed in Chen and Courey, 2000). Groucho proteins have been shown to homo-tetramerize through a glutamine rich Q domain at the N-terminus, and this oligomerization is required for repression. The Q domain is also sufficient for interaction with TCF/LEF proteins (Brantjes et al, 2001; Chen et al, 1998; Pinto and Lobe, 1996; Song et al, 2004). Studies with purified proteins have shown that human TLE1 and 2 bind to an amino-terminal truncated form of LEF1(69-397) with an affinity comparable to that for full length LEF1 (Daniels and Weis, 2005)
TCF7 (TCF1), LEF1, TCF7L1 (TCF3) and TCF7L2 (TCF4) are HMG box-containing DNA-binding proteins that recognize WNT-responsive elements (WREs) in the promoters of WNT target genes. The WRE consensus sequence is CCTTTGWW, where W represents either T or A (reviewed in Brantjes et al, 2002). In the absence of a WNT signal, promoter-bound TCF/LEF is bound by one of four Groucho homologues, TLE1, 2, 3 or 4 (Levanon et al, 1998; Brantjes et al, 2001; Daniels and Weis, 2005). Groucho/TLE proteins are co-repressors for a variety of DNA-binding transcription factors and mediate repression at least in part through their interaction with histone deacetylases such as RPD3/HDAC1 (Arce et al, 2009; Brantjes et al, 2001; Chen et al, 1999; reviewed in Chen and Courey, 2000).
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target gene:TCF/LEF:TLE
tetramertarget genes:TCF/LEF:TLE
tetramer:HDAC1target
genes:TCF/LEFtarget gene
transcriptsAnnotated Interactions
target gene:TCF/LEF:TLE
tetramertarget gene:TCF/LEF:TLE
tetramertarget genes:TCF/LEF:TLE
tetramer:HDAC1target genes:TCF/LEF:TLE
tetramer:HDAC1target
genes:TCF/LEFtarget
genes:TCF/LEFtarget gene
transcriptsUpon WNT3A stimulation, APC K63 polyubiquitination is lost coincident with disruption of the APC-AXIN interaction (Tran and Polakis, 2012). Interestingly, another study has shown that DVL is K63 polyubiquitinated upon WNT signaling (Tauriello et al, 2010), suggesting a possible model in which WNT signaling promotes a change in AXIN-K63 polyubiquitin binding partner to destabilize the destruction complex and promote pathway activation. Alternately, APC K63 polyubiquitination may protect beta-catenin from PP2A-mediated dephosphorylation and thus favour its degradation (Su et al, 2008).