Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling

Abstract

Desmosomal cadherins mediate cell–cell adhesion in epithelial tissues and have been known to be altered in cancer. We have previously shown that one of the two intestinal epithelial desmosomal cadherins, desmocollin-2 (Dsc2) loss promotes colonic epithelial carcinoma cell proliferation and tumor formation. In this study we show that loss of the other intestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithelial cell proliferation and suppressed xenograft tumor growth in mice. Dsg2-deficient cells demonstrated a compensatory increase in Dsc2 expression, and small interfering RNA-mediated loss of Dsc2 restored proliferation in Dsg2-deficient cells. Dsg2 downregulation inhibited epidermal growth factor receptor (EGFR) signaling and cell proliferation through altered phosphorylation of EGFR and downstream extracellular signal-regulated kinase activation in parallel with inhibited EGFR receptor internalization. Additionally, we demonstrated a central role of Dsc2 in controlling EGFR signaling and cell proliferation in intestinal epithelial cells. Consistent with these findings, analyses of human colon cancers demonstrated increased Dsg2 protein expression. Taken together, these data demonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic carcinoma cell proliferation through differential effects on EGFR signaling.

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

“…Altered gene expression indicated the activation of a pathways such as phosphatidylinositol (PI), mitogen-activated protein kinase (MAPK), Wnt, adherens junctions, focal adhesion, and regulation of actin cytoskeleton signaling pathways (3). We also showed that downregulation of DSG2 by small interfering RNA (siRNA) inhibited MAPK signaling (3,37).…”

Galectin-3 Regulates Desmoglein-2 and Intestinal Epithelial Intercellular Adhesion

“…Intercellular junctions are actively remodeled during epithelial proliferation, migration, and differentiation. Intercellular junction proteins regulate signaling events to control these biological processes (1)(2)(3)(4)(5)(6). Thus, altered function of intercellular junction proteins contributes not only to the compromised epithelial barrier but also to changes in epithelial homeostasis observed in disease states associated with mucosal inflammation and neoplasia (1,(7)(8)(9)(10)(11).…”

“…This ability of Gal3 to oligomerize at * This work was supported, in whole or in part, by National Institutes of Health Grants R01 DK072564, R01 DK061379, and R01 DK079392 (to C. A. P.); R01 DK055679 and DK059888 (to A. N.); and DK064399 (National Institutes of Health Digestive Diseases Research Development Center (DDRDC) tissue culture and morphology grant). 1 These two authors should be regarded as co-first authors because they contributed equally to this article. 2 To whom correspondence should be addressed: Dept.…”

150th Anniversary Series: Desmosomes and the Hallmarks of Cancer

“…Early findings showed that expression of desmosomal cadherins inhibits invasive behavior of nonadhesive fibroblasts (Tselepis et al, 1998). Reduced expression of desmosomal cadherins later on was observed in different tumors such as skin Harada et al, 1996;Tada et al, 2000;Xin et al, 2014), head and neck (Shinohara et al, 1998;Wong et al, 2008), lung (Cui et al, 2012a;Cui et al, 2012b), breast (Klus et al, 2001;Oshiro et al, 2005), prostate (Barber et al, 2014;Pan et al, 2014), cervix (Alazawi et al, 2003, uterus (Nei et al, 1996), pancreas (Hamidov et al, 2011), liver (Schüle et al, 2014), gastric (Biedermann et al, 2005;Yashiro et al, 2006), and colon (Cui et al, 2011;Funakoshi et al, 2008;Kamekura et al, 2013;Khan et al, 2006;Knösel et al, 2012;Kolegraff et al, 2011). Taken together, these data suggest a role of desmosomal cadherins as suppressors of tumor metastasis.…”