Molecular physiology and pathophysiology of tight junctions - I. Biogenesis of tight junctions and epithelial polarity

The tight junction (TJ) was first noticed through its ability to control pe rmeation across the paracellular route, but the homologies of its molecular components with peptides that participate in tumor suppression, nuclear ad dressing, and cell proliferation indicate that it may be involved in many o ther fundamental functions. TJs are formed by a dozen molecular species tha t assemble through PDZ and other protein-protein clustering promoting seque nces, in response to the activation of E-cadherin. The TJ occupies a highly specific position between the apical and the basolateral domains. Its firs t molecular components seem to be delivered to such a position by addressin g signals in their molecule and, once anchored, serve as a clustering nucle us for further TJ-associated molecules. Although in mature epithelial cells TJs and E-cadherin do not colocalize, a complex chain of reactions goes fr om one to the other that involves alpha-, beta-, and gamma-catenins, two di fferent G proteins, phospholipase C, protein kinase C, calmodulin, mitogen- activated protein kinase, and molecules pertaining to the cytoskeleton, whi ch keep the TJ sensitive to physiological requirements and local conditions (notably to Ca2+-dependent cell-cell contacts) throughout the life of the epithelium.