This is a stub page. Please help us describe more about regulation of tight junction assembly in mechanobiology by editing this page.
The physiological properties of the epithelium are determined by the formation of epithelial tight junctions and are regulated by factors that modulate the molecular organization of these junctional complexes.
Tight junctions are constituted by several transmembrane proteins, which form homophilic and heterophilic interactions with transmembrane proteins on adjacent cell surfaces. Adhesive contacts between cells are primarily established through claudin strands, while other transmembrane proteins such as occludin, tricellulin and junctional adhesion molecules (JAMs) function in stabilizing the initial adhesions and in regulating junctional properties in response to stimuli . Though tight junctions were shown to form even in the absence of occludin , studies have suggested a key role for this protein in tight junction function by regulating claudin composition at the junctions . Caesin kinase 2-mediated phosphorylation of occludin cytoplasmic residues has been shown to regulate epithelial permeability by altering protein dynamics at the tight junctions .
Tight junction assembly is also mediated by linkages to a cytosolic scaffold that contains several adaptors and signaling molecules. Zonula occludens-1 and -2 (ZO-1 and ZO-2), which are the best-studied cytosolic adaptors, regulate epithelial permeability by recruiting claudin-1 and claudin-2 to the cell junctions through PDZ1-mediated interactions. The continuous, circumferential distribution of claudins is also reliant on PDZ2-mediated ZO dimerization. Additionally, PDZ1-regulated actomyosin distribution at the apical junctions is essential for stabilizing tight junction structure . Other cytoplasmic tight junction proteins, cingulin and paracingulin, also regulate claudin levels through GATA-4 (a transcription factor) and RhoA-dependent processes .
Tight junctions are also stabilized by their physical association with cytoskeletal networks of actin, microtubule and intermediate filaments. Dynamic remodeling of the cytoskeleton regulates junction assembly and function. The presence of a perijunctional actomyosin bundle at the junctional complexes of brush border epithelium was described in the 1970s  and recent studies have affirmed the role of actin and myosin isoforms in the regulation of tight junctions. Both beta- and gamma-actin are essential for tight junction assembly with additional roles for beta-actin in the maintenance of apico-basal polarity . Nonmuscle myosin II heavy chain isoform A (Myosin IIA) facilitates junction assembly by regulating perijunctional actin filament organization . In addition to the actomyosin bundle, a polarized network of microtubules at the junction promotes assembly by recruiting E-cadherin to the apical junctional complexes . Recent work by Yano et al. revealed the presence of an additional planar apical network of microtubules that are anchored to tight junctions through phosphorylated cingulin, and a role for this new microtubule network in tight junction-associated epithelial morphogenesis .
Cytoskeletal reorganization at the tight junctions is regulated by a coordinated interplay of the Rho GTPases and their effectors. Activated Rac and Cdc42 promote actin polymerization by recruiting actin regulators such as cortactin, Arp2/3 complex, WAVE and N-WASP to the junctions , with dominant negative or constitutively active GTPase mutants leading to impairment of both the barrier and fence functions of tight junctions . RhoA signaling pathways, mediated by effectors mDia and ROCK, are also known to promote tight junction assembly by regulating actin filament organization .
Several physiological and pathophysiological stimuli such as SGLT-1 (sodium-glucose cotransporter) activation, TNF-LIGHT and IL-1β modulate tight junction structure by altering the distribution of tight junction proteins such as ZO-1, ZO-2 and occludin, which leads to enhanced epithelial permeability . MLCK-induced events such as phosphorylation of myosin light chains leads to enhanced actomyosin contractility and redistribution of tight junction proteins, both of which contribute to barrier disruption and increased permeability . Impaired barrier properties are implicated in chronic mucosal inflammation and in the pathogenesis of inflammatory conditions such as asthma, cystic fibrosis, and Crohn’s disease .