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Loss of Desmocollin-2 Confers a Tumorigenic Loss of desmocollin-2 confers a tumorigenic phenotype to colonic epithelial cells through activation of Akt/β-catenin signaling Keli Kolegraff, Emory University Porfirio Nava Dominguez, Emory University My Nga Helms, Emory University Charles Parkos, Emory University Asma Nusrat, Emory University Journal Title: Molecular Biology of the Cell Volume: Volume 22, Number 8 Publisher: American Society for Cell Biology | 2011-04-15, Pages 1121-1134 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1091/mbc.E10-10-0845 Permanent URL: http://pid.emory.edu/ark:/25593/f7287 Final published version: http://www.molbiolcell.org/content/22/8/1121 Copyright information: © 2011 Kolegraff et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/). Accessed September 27, 2021 5:31 PM EDT M BoC | ARTICLE Loss of desmocollin-2 confers a tumorigenic phenotype to colonic epithelial cells through activation of Akt/β-catenin signaling Keli Kolegraffa,*, Porfirio Navaa,*, My N. Helmsb, Charles A. Parkosa, and Asma Nusrata aEpithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine and bDepartment of Physiology, Emory University School of Medicine, Atlanta, GA 30322 ABSTRACT Desmocollin-2 (Dsc2) and desmoglein-2 (Dsg2) are transmembrane cell adhesion Monitoring Editor proteins of desmosomes. Reduced expression of Dsc2 has been reported in colorectal carci- Ben Margolis nomas, suggesting that Dsc2 may play a role in the development and/or progression of col- University of Michigan Medical School orectal cancer. However, no studies have examined the mechanistic contribution of Dsc2 de- ficiency to tumorigenesis. Here we report that loss of Dsc2 promotes cell proliferation and Received: Oct 22, 2010 enables tumor growth in vivo through the activation of Akt/β-catenin signaling. Inhibition of Revised: Jan 3, 2011 Akt prevented the increase in β-catenin–dependent transcription and proliferation following Accepted: Feb 3, 2011 Dsc2 knockdown and attenuated the in vivo growth of Dsc2-deficient cells. Taken together, our results provide evidence that loss of Dsc2 contributes to the growth of colorectal cancer cells and highlight a novel mechanism by which the desmosomal cadherins regulate β-catenin signaling. INTRODUCTION Colorectal cancer is a leading cause of cancer morbidity and mortal- occur throughout the evolution of the tumor; however, hyperactiva- ity worldwide (Jemal et al., 2008). In the United States alone, 160,000 tion of the Wnt/β-catenin signaling pathway is largely regarded as people are diagnosed with colorectal cancer every year, and close the initiating event underlying colorectal cancer development, and to 60,000 of these patients will die from their disease (Markowitz sustained activation of β-catenin signaling is required for tumor pro- and Bertagnolli, 2009). Colorectal cancer begins as a benign ade- gression (Oving and Clevers, 2002; Gavert and Ben-Ze’ev, 2007; noma and progresses through the adenoma–carcinoma sequence Markowitz and Bertagnolli, 2009). to eventually acquire features of an invasive cancer with metastatic In the normal adult intestinal epithelium, Wnt/β-catenin signal- potential (Humphries and Wright, 2008). Numerous genetic changes ing preserves the crypt stem cell population and drives epithelial cell proliferation, thereby contributing to epithelial cell renewal and This article was published online ahead of print in MBoC in Press (http://www the maintenance of tissue homeostasis (Pinto and Clevers, 2005). .molbiolcell.org/cgi/doi/10.1091/mbc.E10-10-0845) on February 16, 2011. Central to the regulation of Wnt/β-catenin signaling is the control of *These authors contributed equally to this work. the protein stability of β-catenin, the core effector molecule of this The authors have no competing financial interests in relation to the work de- pathway. In the absence of the appropriate Wnt signals, β-catenin is scribed herein. targeted for degradation by a destruction protein complex—con- Address correspondence to: Asma Nusrat ([email protected]). taining Axin, glycogen synthase kinase 3β (GSK-3β), and adenoma- Abbreviations used: APC, adenomatous polyposis coli; DMSO, dimethyl sulfox- ide; Dsc2, desmocollin-2; Dsg2, desmoglein-2; EdU, 5-ethynyl-2′-deoxyuridine; tous polyposis coli (APC)—which binds to and phosphorylates the EGFR, epidermal growth factor receptor; FCS, fetal calf serum; GAPDH, glyceral- N-terminus of β-catenin, leading to its ubiquitination and degrada- dehyde-3-phosphate dehydrogenase; GSK-3β, glycogen synthase kinase 3β; HBSS, Hank’s balanced salt solution; mAb, monoclonal antibody; pAb, polyclonal tion by the proteasome (Jin et al., 2008). Inhibition of the destruc- antibody; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-kinase; PIP3, tion complex allows the cytosolic accumulation and nuclear localiza- phosphatidylinositol-(3,4,5)-triphosphate; RT, room temperature; SEM, standard tion of β-catenin, where it cooperates with T-cell factor (TCF)/ error of the mean; shRNA, short-hairpin RNA; siRNA, small interfering RNA; TCF, T-cell factor. lymphoid enhancer factor family members to mediate the transcrip- © 2011 Kolegraff et al. This article is distributed by The American Society for Cell tion of proproliferative genes (Clevers, 2006). The most common Biology under license from the author(s). Two months after publication it is avail- mutations in colorectal cancer inactivate the gene that encodes able to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). APC, leading to constitutive activation of Wnt/β-catenin signaling “ASCB®,“ “The American Society for Cell Biology®,” and “Molecular Biology of and hyperproliferation of cells. Other mutations include those in the the Cell®” are registered trademarks of The American Society of Cell Biology. N-terminal sequence of β-catenin, which interfere with the ability to Supplemental Material can be found at: Volume 22 April 15, 2011 http://www.molbiolcell.org/content/suppl/2011/02/14/mbc.E10-10-0845.DC1.html 1121 phosphorylate and degrade the protein (Markowitz and Bertagnolli, Wang et al., 2007). To investigate whether Dsc2 influences 2009). In addition to Wnt signaling and regulation via the destruc- β-catenin signaling in colonic epithelial cells, we down-regulated tion complex, Wnt-independent mechanisms also modulate Dsc2 expression in SK-CO15 cells using RNA interference. Dsc2 β-catenin–dependent transcription. Notably, regulation of β-catenin down-regulation was confirmed by immunoblot analysis and im- by the cadherin family of cell adhesion molecules has received sig- munofluorescence labeling/confocal microscopy (Figure 1A). nificant attention in the field of tumor biology and, more recently, Dsc2-specific small interfering RNA (siRNA) did not decrease the the PI3K/Akt signaling axis has been shown to promote β-catenin total protein levels of other cadherin superfamily members Dsg2 signaling and cell proliferation in mouse models of intestinal car- or E-cadherin (E-cad), thus demonstrating the specificity of the cinogenesis and inflammation (He et al., 2004, 2007; Lee et al., siRNA for Dsc2 (Figure 1A). To assess β-catenin following Dsc2 2010; Nava et al., 2010). knockdown, we first examined total protein levels of β-catenin by Classical cadherins such as E-cadherin and N-cadherin directly immunoblotting. Dsc2 down-regulation did not significantly alter bind β-catenin, and this interaction is essential for their function as total levels of β-catenin (Figure 1B). However, because total pro- cell adhesion proteins (Nelson and Nusse, 2004). In addition, by as- tein levels of β-catenin do not necessarily correlate with its tran- sociating with β-catenin, these proteins sequester β-catenin at the scriptional activity, we also used a luciferase-based transcriptional cell membrane and antagonize its transcriptional activity in colon reporter assay (TOP Flash) to measure β-catenin–dependent tran- cancer cells (Sadot et al., 1998; Gottardi et al., 2001; Stockinger scription in cells with decreased Dsc2 expression (Korinek et al., et al., 2001). Down-regulation of E-cadherin has been shown to pro- 1997). Cells were cotransfected with control or Dsc2-specific siRNA mote β-catenin/TCF transcription in a number of cancer cell types and the TOP reporter plasmid containing the β-catenin/TCF bind- (Eger et al., 2000; Kuphal and Behrens, 2006), and this is one gen- ing motifs. A parallel set of cotransfections was carried out using eral mechanism by which loss of cell adhesion proteins is thought to the FOP plasmid with mutated binding sites as a negative control. contribute to tumor progression. At 72 h after transfection, luciferase activity was assessed in control Desmosomal cadherins, consisting of desmocollin (Dsc 1–3) and and Dsc2-deficient cells. As shown in Figure 1C, β-catenin/TCF desmoglein (Dsg 1–4) family members in humans, do not interact signaling was significantly increased approximately fivefold in cells with β-catenin (Kowalczyk et al., 1994b; Wahl et al., 2000) but have with decreased Dsc2 expression. Importantly, down-regulation of been
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