Activation of RON differentially regulates claudin expression and localization: role of claudin-1 in RON-mediated epithelial cell motility

Carcinogenesis
Kun ZhangMing-Hai Wang

Abstract

Claudins are integral membrane proteins essential in tight junction formation and function. Altered expression of claudins has been implicated in epithelial malignant transformation. We report here that activation of recepteur d'origine nantais (RON) differentially regulates tight junction function and claudin expression. In Martin-Darby canine kidney (MDCK) cells, macrophage-stimulating protein-induced RON activation or expression of constitutively active variant RON160 significantly disrupted cellular tight junctions and reduced transepithelial electrical resistance. These changes were featured by diminished claudin-1 expression and redistribution of claudin-3 and -4 into cytoplasmic compartments. The inhibition of claudin-1 was also seen in breast cancer T-47D cells. By analyzing the signaling events, we found that activation of the extracellular signal-regulated kinase 1/2 pathway is required for RON-mediated inhibition of claudin-1 expression and redistribution of claudin-3 and -4. Results from luciferase reporter assays showed that inhibition is acted at the transcriptional levels because RON activation decreases claudin-1 promoter activities and increases transcriptional repressor Snail-1 expression. Functional analysis ...Continue Reading

Citations

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