Abstract
Adherens junction (AJ) is a specialized cell-cell junction structure that plays a role in mechanically connecting adjacent cells to resist strong contractile forces and to maintain tissue structure, particularly in the epithelium. AJ is mainly comprised of cell adhesion molecules cadherin and nectin and their associating cytoplasmic proteins including β-catenin, α-catenin, p120(ctn), and afadin. Our series of studies have revealed that nectin first forms cell-cell adhesion and then recruits cadherin to form AJ. The recruitment of cadherin by nectin is mediated by the binding of α-catenin and p120(ctn) to afadin. Recent studies showed that PLEKHA7 binds to p120(ctn), which is associated with E-cadherin, and maintains the integrity of AJ in epithelial cells. In this study, we showed that PLEKHA7 bound to afadin in addition to p120(ctn) and was recruited to the nectin-3α-based cell-cell adhesion site in a manner dependent on afadin, but not on p120(ctn). The binding of PLEKHA7 to afadin was required for the proper formation of AJ, but not for the formation of tight junction, in EpH4 mouse mammary gland epithelial cells. These results indicate that PLEKHA7 plays a cooperative role with nectin and afadin in the proper formation of AJ in epithelial cells.
Highlights
Afadin is an important regulator of cell-cell adhesion
We have shown here that: 1) PLEKHA7 binds to afadin in addition to p120ctn; 2) PLEKHA7 is recruited to the nectin-3␣-based cellcell adhesion site by binding to afadin in a p120ctn-independent manner; and 3) PLEKHA7 is recruited to the E-cadherin-based cell-cell adhesion site in an afadin-independent manner
The ability of PLEKHA7 to bind to afadin is not sufficient to explain its strict localization at adherens junction (AJ), because PLEKHA7 is able to bind to p120ctn, which is localized at both AJ and the basal side of AJ along the lateral plasma membranes of attached cells, and PLEKHA7 is recruited to the E-cadherin-based cell-cell adhesion site in an afadin-independent manner in EL cells (Fig. 4)
Summary
Afadin is an important regulator of cell-cell adhesion. Results: PLEKHA7 binds to afadin and this binding is required for the proper formation of adherens junction (AJ). During and/or after the formation of AJ, nectin recruits first junctional adhesion molecule and claudin and occludin to the apical side of AJ, resulting in the formation of TJ It remains unknown how the trans-interactions of nectin lead to the recruitment of the TJ components, but afadin and ZO-1 and the interaction of these two proteins are necessary for the recruitment of CAMs to TJ [15]. We found that this binding of PLEKHA7 to afadin was required for the proper formation of AJ, but not for the formation of TJ, in EpH4 mouse mammary gland epithelial cells We show here this novel regulatory mechanism for the formation of AJ in epithelial cells
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