Epidermal Growth Factor Receptor Activation Differentially Regulates Claudin Expression and Enhances Transepithelial Resistance in Madin-Darby Canine Kidney Cells

Singh, Amar B.; Harris, Rayrnond C.

doi:10.1074/jbc.m308682200

Cited by 175 publications

(174 citation statements)

References 60 publications

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“…Thus, claudin-2 expression in MDCKII cells is regulated through at least two independent pathways, involving RhoA and JNK, respectively. Previous studies have indicated an involvement of the ERK pathway in the regulation of claudin-2 expression (Kinugasa et al, 2000;Lan et al, 2004;Singh and Harris, 2004;Yamamoto et al, 2004;Murata et al, 2005). However, treatment of only MDCKI, but not MDCKII cells, with the ERK inhibitor U0126 up-regulates claudin-2, suggesting that the ERK pathway is not implicated in the up-regulation of claudin-2 expression in MDCKII cells (Lipschutz et al, 2005).…”

Section: Discussionmentioning

confidence: 78%

“…The MAPK/extracellular signal-regulated kinase (ERK) kinase pathway has been implicated in the control of claudin-2 expression (Kinugasa et al, 2000;Lan et al, 2004;Singh and Harris, 2004;Yamamoto et al, 2004;Lipschutz et al, 2005;Murata et al, 2005). To investigate the role of this and other signaling pathways in the up-regulation of claudin-2 and ZO-3 in cingulin KD clones, cingulin-depleted cells were treated with either the MAPK/ERK inhibitor U0126, the p38 kinase inhibitor SB202190, or the JNK inhibitor SP600125 ( Figure 3A).…”

Section: Jnk Regulate Claudin-2 Expression Independently Of Cingulin mentioning

confidence: 99%

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Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Guillemot

Citi

2006

MBoC

100

138

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In mouse embryoid bodies, mutation of the tight junction protein cingulin results in changes in gene expression. Here, we studied the function of cingulin using a gene silencing approach in Madin-Darby canine kidney (MDCK) cells. Cingulin-depleted cells show higher protein and mRNA levels of claudin-2 and ZO-3, increased RhoA activity, activation of G 1 /S phase transition, and increased cell density. The effects of cingulin depletion on claudin-2 expression, cell proliferation, and density are reversed by coexpression of either a dominant-negative form of RhoA (RhoAN19) or the Rho-inhibiting enzyme C3 transferase. However, the increase in ZO-3 protein and mRNA levels is not reversed by inhibition of either RhoA, p38, extracellular signal-regulated kinase (ERK), or c-Jun NH 2 -terminal kinase (JNK), suggesting that cingulin modulates ZO-3 expression by a different mechanism. JNK is implicated in the regulation of claudin-2 levels independently of cingulin depletion and RhoA activity, indicating distinct roles of RhoA-and JNK-dependent pathways in the control of claudin-2 expression. Finally, cingulin depletion does not significantly alter the barrier function of monolayers and the overall molecular organization of tight junctions. These results provide novel insights about the mechanisms of cingulin function and the signaling pathways controlling claudin-2 expression in MDCK cells.

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Section: Discussionmentioning

confidence: 78%

Section: Jnk Regulate Claudin-2 Expression Independently Of Cingulin mentioning

confidence: 99%

Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Guillemot

Citi

2006

MBoC

100

138

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“…It is therefore reasonable that down-regulation of claudin-2, as we observe in this study of ras-transfection, results in increased transepthelial electrical resistance. Elevation of transepithelial electrical resistance caused by exposure to EGF was likewise observed to coincide with decreased expression of claudin-2 (Singh and Harris, 2004).…”

Section: Discussionmentioning

confidence: 83%

RasMutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

Mullin

Leatherman

Valenzano

et al. 2005

MBoC

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Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK 1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of D-mannitol increases sixfold but transepithelial electrical resistance increases >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to D-mannitol (M r 182), polyethylene glycol (M r 4000), and 10,000-M r methylated dextran but not to 2,000,000-M r methylated dextran. This implies a "ceiling" on the size of solutes that can cross a ras-mutated epithelial barrier and therefore that the increased permeability is not due to loss of cells or junctions. Although the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins-3 and -5 remained unchanged. An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier. INTRODUCTIONMutations in the three closely related ras genes, H-ras, K-ras, and N-ras, are among the most common mutations found in human cancer, reaching 50% in some types of tumors, such as colorectal carcinoma (Forrester et al., 1987;Andreyev et al., 1997Andreyev et al., , 1998Andreyev et al., , 2001). Vogelstein and colleagues have shown that mutations in K-ras occur early in the development of colon carcinomas (Vogelstein et al., 1988). This dominantly acting mutation in ras results in its constitutive activation and the subsequent triggering of its signaling pathway by influencing GTPase activity. It is clear that mutations in ras contribute both to the recurrence of the disease and to decreased survival (Andreyev et al., 1998). It is less clear, however, what the consequences of ras mutations are during the early stages of tumorigenesis. In this regard, one important issue is the effect of Ras activation on epithelial barrier function, perhaps the most basic of all epithelial functions, and a function shared by all epithelial tissues. Ras can exert fundamental effects on epithelial barrier function through the extracellular signal-regulated kinase-mitogen-activated protein (ERK-MAP) kinase pathway or through direct binding to the tight junction-associated protein, AF-6, which binds to ZO-1, which in turn links the tight junction to the actin cytoskeleton. Activated Ras is known to inhibit interaction between the tight junction-associated proteins, AF-6 and ZO-1, with resultant perturbation of intercellular junctions (Yamamoto et al., 1997). Modulation of tight junctions by G proteins in ge...

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“…As a simple example, in the case of the epithelial-mesenchymal transition, the overall expression levels of claudins were decreased (Ikenouchi et al, 2003). In the presence of HGF and EGF, some claudins were reportedly upregulated whereas others were downregulated (Singh and Harris, 2004). Furthermore, even when the expression levels did not change, it was reported that the localizations of claudins were altered (Lioni et al, 2007).…”

Section: Changes In the Expression Levels Of Claudins Induced By Carcmentioning

confidence: 99%

Tight junction-based epithelial microenvironment and cell proliferation

et al. 2008

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Epidermal Growth Factor Receptor Activation Differentially Regulates Claudin Expression and Enhances Transepithelial Resistance in Madin-Darby Canine Kidney Cells

Cited by 175 publications

References 60 publications

Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

Cingulin Regulates Claudin-2 Expression and Cell Proliferation through the Small GTPase RhoA

RasMutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

Tight junction-based epithelial microenvironment and cell proliferation

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