DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin.

Yi-Chun Yeh, Chia-Ching Wu, Yang-Kao Wang, Ming-Jer Tang

Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.

Molecular biology of the cell 2011 Apr

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Discoidin domain receptor 1 (DDR1) promotes E-cadherin-mediated adhesion. The underlying mechanism and its significance, however, have not been elucidated. Here we show that DDR1 overexpression augmented, whereas dominant negative mutant (DN-DDR1) or knockdown of DDR1 inhibited E-cadherin localized in cell-cell junctions in epithelial cells. DDR1 changed the localization and abundance of E-cadherin, as well as epithelial plasticity, as manifested by enhancement of microvilli formation and alteration of cytoskeletal organization. DDR1 also reduced protein abundance of mesenchymal markers, whereas DN-DDR1 and sh-DDR1 showed opposite effects. These results suggest that expression of DDR1 increases epithelial plasticity. Expression of DDR1 augmented E-cadherin protein levels by decreasing its degradation rate. Photobleaching and photoconversion of E-cadherin conjugated with Eos fluorescence protein demonstrated that DDR1 increased the stability of E-cadherin on the cell membrane, whereas sh-DDR1 decreased it. Pull-down assay and expression of constitutively active or dominant-negative Cdc42 showed that DDR1 stabilized E-cadherin through inactivation of Cdc42. Altogether, our results show that DDR1 promotes cell-cell adhesion and differentiation through stabilization of E-cadherin, which is mediated by Cdc42 inactivation.

Citation

Yi-Chun Yeh, Chia-Ching Wu, Yang-Kao Wang, Ming-Jer Tang. DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin. Molecular biology of the cell. 2011 Apr;22(7):940-53