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

Jiang, Kun; Rankin, Carl R.; Nava, Porfirio; Sumagin, Ronen; Kamekura, Ryuta; Stowell, Sean R.; Feng, Mingli; Parkos, Charles A.; Nusrat, Asma

doi:10.1074/jbc.m113.538538

Cited by 45 publications

(46 citation statements)

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“…Loss of Dsg‐2 reduces intercellular adhesion strength, leading to impaired IEC monolayer integrity (40). Given our observation of PMN‐MP‐mediated cleavage of Dsg‐2, we used a well‐established Dispase assay (40) to examine whether PMN and PMN‐MP binding to IECs could disrupt the integrity of monolayers. PMN adhesion to IECs (2 × 10 6 cells/well in a 6‐well plate, 3 h, 37°C) induced by fMLF (100 nM, had no effect on IECs) triggered a robust fragmentation of epithelial monolayers (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether Dsg‐2 contributes to the regulation of PMN TEM and confirm that the observed PMNMP effects were due to loss of Dsg‐2, PMN TEM was examined after siRNA–mediated down‐regulation of Dsg‐2 or after IEC treatment with an inhibitory anti‐galectin (Gal)‐3 antibody (M3/38). We recently established that M3/38 inhibits Gal‐3 binding to Dsg‐2, leading to its depletion from epithelial junctions (40). For both treatments, down‐regulation of Dsg‐2 resulted in significant increases in PMN TEM (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration

et al. 2016

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Neutrophil [polymorphonuclear leukocyte (PMN)] transepithelial migration (TEM) is a hallmark of inflammatory mucosal disorders. PMN TEM is associated with epithelial injury; however, mechanisms involved in this process are not well defined. The current work describes a new mechanism whereby deposition of PMN membrane-derived microparticles (PMN-MPs) onto intestinal epithelial cells (IECs) during TEM leads to loss of epithelial cadherins, thus promoting epithelial injury and increased PMN recruitment. PMN-MPs secreted by activated PMNs during TEM displayed a high level of enzymatically active matrix metalloproteinase 9 (MMP-9), and were capable of mediating potent effects on IEC integrity. Isolated PMN-MPs efficiently bound to IEC monolayers and induced cleavage of desmoglein-2 (DSG-2) but not E-cadherin, leading to disruption of IEC intercellular adhesions. Furthermore, PMN-MP binding to intestinal epithelium in vitro in transwell assays and in vivo in ligated intestinal loop preparations facilitated increases in PMN TEM. These effects were MMP-9 dependent and were reversed in the presence of specific pharmacological inhibitors. Finally, we demonstrated that IEC Dsg-2 serves as a barrier for migrating PMNs, and its removal by PMN-MP-associated MMP-9 facilitates PMN trafficking across epithelial layers. Our findings thus implicate PMN-MPs in PMN-mediated inflammation and epithelial damage, as observed in inflammatory disorders of mucosal surfaces.-Butin-Israeli, V., Houser, M. C., Feng, M., Thorp, E. B., Nusrat, A., Parkos, C. A, Sumagin, R. Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration

et al. 2016

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“…Thus, our finding here that Dsg2 can modulate EGFR activation is a critical link that connects cell-cell adhesion to mitogenic signaling in skin cancer development. Dsg2 depletion in SK-CO15 colon cancer cells also disrupts EGFR signaling [56]. However unlike HaCaT keratinocytes, loss of Dsg2 does not alter the total level of EGFR in SK-CO15 colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

c-Src/Cav1-dependent activation of the EGFR by Dsg2

et al. 2016

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The desmosomal cadherin, desmoglein 2 (Dsg2), is deregulated in a variety of human cancers including those of the skin. When ectopically expressed in the epidermis of transgenic mice, Dsg2 activates multiple mitogenic signaling pathways and increases susceptibility to tumorigenesis. However, the molecular mechanism responsible for Dsg2-mediated cellular signaling is poorly understood. Here we show overexpression as well as co-localization of Dsg2 and EGFR in cutaneous SCCs in vivo. Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation. To determine whether Dsg2 mediates signaling through lipid microdomains, sucrose density fractionation illustrated that Dsg2 is recruited to and displaces Cav1, EGFR and c-Src from light density lipid raft fractions. STED imaging confirmed that the presence of Dsg2 disperses Cav1 from the cell-cell borders. Perturbation of lipid rafts with the cholesterol-chelating agent MβCD also shifts Cav1, c-Src and EGFR out of the rafts and activates signaling pathways. Functionally, overexpression of Dsg2 in human SCC A431 cells enhances EGFR activation and increases cell proliferation and migration through a c-Src and EGFR dependent manner. In summary, our data suggest that Dsg2 stimulates cell growth and migration by positively regulating EGFR level and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms.

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“…Finally, at the cell surface specific factors may stabilize desmosomal cadherins as shown for Dsg2 in association with the lectin galectin-3 (Gal3). In the absence of Gal3, Dsg2 is internalized (Jiang et al, 2014). However, it cannot be excluded that half-desmosomes pre-assemble in the membrane and attach with counterparts on the opposing cell surface to establish a mature desmosome (Demlehner et al, 1995).…”

Section: Impaired Transport Targeting and Assembly Into Mature Desmmentioning

confidence: 98%

150th Anniversary Series: Desmosomes and the Hallmarks of Cancer

Huber

Petersen

2015

Cell Communication & Adhesion

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Desmosomes represent adhesive, spot-like intercellular junctions that in association with intermediate filaments mechanically link neighboring cells and stabilize tissue architecture. In addition to this structural function, desmosomes also act as signaling platforms involved in the regulation of cell proliferation, differentiation, migration, morphogenesis, and apoptosis. Thus, deregulation of desmosomal proteins has to be considered to contribute to tumorigenesis. Proteolytic fragmentation and downregulation of desmosomal cadherins and plaque proteins by transcriptional or epigenetic mechanisms were observed in different cancer entities suggesting a tumor-suppressive role. However, discrepant data in the literature indicate that context-dependent differences based on alternative intracellular, signal transduction lead to altered outcome. Here, modulation of Wnt/β-catenin signaling by plakoglobin or desmoplakin and of epidermal growth factor receptor signaling appears to be of special relevance. This review summarizes current evidence on how desmosomal proteins participate in carcinogenesis, and depicts the molecular mechanisms involved.

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

Cited by 45 publications

References 58 publications

Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration

Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration

c-Src/Cav1-dependent activation of the EGFR by Dsg2

150th Anniversary Series: Desmosomes and the Hallmarks of Cancer

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