Modification of tight junction function by protein kinase C isoforms

The regulation of tight junction permeability by a variety of signal transd uction pathways is summarized. An emphasis is placed on regulation of parac ellular permeability by the protein kinase C family of isoforms, which invo lves the reporting of a large number of studies using the phorbol ester fam ily of protein kinase C activators. The ability of protein kinase C activat ion to open epithelial barriers to a very wide range of solutes is emphasiz ed, but then countered with discussion of the role of phorbol esters and pr otein kinase C activation in epithelial carcinogenesis. The ability of prot ein kinase C activation to enable growth factors to leak from luminal fluid compartments of epithelial tissues into lateral intercellular and intersti tial fluid spaces may play a role in this carcinogenic action. An examinati on of protein kinase C effects on the phosphorylation states of tight junct ional proteins suggests that downstream kinases and/or phosphatases mediate protein kinase C's effect on tight junction permeability. A role for prote in kinase C in transepithelial drug delivery is questioned herein. The tigh t junctional leakiness associated with protein kinase C activation and appa rently intrinsic to transformed epithelia suggests a potentially useful rol e for tight junction leakiness as a marker for early cancer diagnosis. (C) 2000 Elsevier Science B.V. All rights reserved.