Tight Junctions Proteins

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 Tight Junctions Proteins Background

Tight junctions

Cell-cell interactions are important to multi-cellular organisms in both physiological and pathological states. For example, the assembly of tissues and their organization into organs would not be possible without the expression of junctional complexes that allow cells to interact with other cells and with the extracellular matrix. Interactions between cells, between cells and the extracellular matrix, and between cells and the external environment are important to many physiological processes such as cell survival, development, proliferation, differentiation, adhesion and migration. The four major intercellular junctions are comprised of multi-protein complexes that include both intracellular and intercellular transmembrane protein components, and can be functionally categorized into occluding junctions (tight junctions), anchoring junctions (adherens junctions and desmosomes), and communicating junctions (gap junctions). Occluding junctions include tight junctions, which seal cells together to prevent para-cellular transport of small molecules. Anchoring junctions serve to attach cells to each other and to the extra-cellular matrix. These junctions include adherens junctions, which serve as connection sites for actin filaments and desmosomes, which serve as connection sites for intermediate filaments. Lastly, communicating junctions include gap junctions, which serve to mediate passage of chemical and electrical signals between connected cells.

Tight junctions form as a series of contacts between the plasma membranes of adjacent cells. They are multiprotein complexes composed of occludins, claudins, and zonula occludins. The transmembrane proteins, occludins and claudins, polymerize together to form strands in the intercellular space. Claudins contribute to the majority of the sealing actions of tight junctions. The carboxy terminal portions of occludins and claudins bind to the scaffolding protein, zonula occludins. Zonula occludins associate with actin and myosin that form an actomyosin ring in the apical section of the cell, providing a physical regulatory link to the cell’s cytoskeleton. Tight junctions also contain cholesterol rich membrane domains, important in the regulation of paracellular permeability. The lipid raft structures associate with occludin, claudins, JAM-A, and ZO-1 proteins of tight junctions. The disassembly of these tight junction proteins from their associated lipid rafts induces paracellular permeability. The mechanism by which tight junctions assemble and disassemble under various conditions is not fully defined.

Tight junctions have two important roles within epithelial and endothelial cells. The first major function of tight junctions is to form a regulated, semipermeable barrier, responsible for segregating proteins of the apical and basolateral plasma membrane domains. This fence function of tight junctions is important in maintaining the distinctive microenvironments of the apical/basolateral polarity of cells. The second function of tight junctions is to regulate passive diffusion of solutes through the paracellular pathway. Tight junctions can selectively permit the passage of ions and molecules through the paracellular pathway by discrimination of their size and charge. Importantly, tight junctions also physically segregate unwanted solutes and microorganisms in the lumen of tissue/organ systems from entering the interstitium.

Tight junction function is dependent on signal transduction cascades that act on the actin cytoskeleton. When contraction of the actomyosin ring is induced, the tight junctions are disassembled and the paracellular pathway is opened for free movement of solutes. Researchers, including our lab, have coupled regulation of tight junction function with the activities of Rho kinase (ROCK), myosin light chain kinase (MLCK), and myosin regulatory light chain 2 (MLC). The state of MLC determines whether actomyosin contraction is induced and tight junctions are destabilized. When MLC is phosphorylated, actomyosin contracts and tight junctions disassemble and vice versa. ROCK and MLCK work together to regulate the phosphorylation state of MLC and consequently its activity. ROCK and MLCK work like a biological ON/OFF switch activating or inactivating MLC. Which enzyme serves as the ON switch and which serves as the OFF is cell type dependent. For example, in Caco-2 cells, a human colon epithelial cell line, MLCK activity destabilizes tight junctions resulting in a loss in barrier function measured as increased permeability. In Calu-3 cells, a human lung epithelial cell line, MLCK function stabilizes tight junctions resulting in maintenance of barrier function, while ROCK increases barrier permeability. How this ON/OFF switching system is regulated is still unclear, as is the basis for the cell type specificity.