The organization of tight junctions in epithelia: implications for mammary gland biology and breast tumorigenesis

Abstract

Tight junctions (TJs), the most apical components of the cell-cell junctional complexes, play a crucial role in the establishment and maintenance of cell polarity within tissues. In secretory glandular tissues, such as the mammary gland, TJs are crucial for separating apical and basolateral domains. TJs also create the variable barrier regulating paracellular movement of molecules through epithelial sheets, thereby maintaining tissue homeostasis. Recent advances reveal that TJs exist as macromolecular complexes comprised of several types of membrane proteins, cytoskeletal proteins, and signaling molecules. Many of these components are regulated during mammary gland development and pregnancy cycles, and several have received much attention as possible "tumor suppressors" during progression to breast cancer.

Fig. 1

(A) Ultrastructural image of a tight junction captured with a transmission electron microscope using thin-sectioned intestinal epithelial cells. Arrows indicate “kissing points,” an indistinguishable distance between two adjacent cell membranes; Mv, microvilli; TJ, tight junction. (B) Tight junction strands visualized by freeze-fracture replica electron microscopy of intestinal epithelial cells. Tight junction strands are observed as a network of continuous and anastomosing intramembranous particles of fibrillary strands on the protoplasmic face (arrows), with complementary vacant grooves on the exoplasmic face (arrowheads); Mv, microvilli (Courtesy of S. Tsukita et al., from Nat. Rev. Mol. Cell Biol. 2001;2:285–293).

Fig. 2

(A) Direct interactions between TJ membrane proteins and PDZ proteins. ZO-1, ZO-2, and ZO-3 bind to occludin and claudins through the GUK and PDZ1 domain, respectively. PDZ9 and PDZ10 of MUPP1 bind to claudins and JAM, respectively. JAM associates with ZO-1 through its PDZ3 domain and with PAR-3 through its PDZ1 domain. The specific binding domains to each membrane proteins in PDZ proteins are highlighted. (B) Schematic representative of the molecular organization of TJs. TJ strands mainly consist of claudins. However, evidence suggests that occludin and JAM are also incorporated into TJ strands via interaction with PDZ proteins. PDZ proteins associate with each other, with other cytoplasmic components such as non-PDZ proteins and signaling molecules, and with actin filaments. Thus, PDZ proteins function as a scaffold to organize multiple protein networks at TJs.