Modification of tight junction function by protein kinase C isoforms.
The regulation of tight junction permeability by a variety of signal transduction pathways is summarized. An emphasis is placed on regulation of paracellular permeability by the protein kinase C family of isoforms, which involves the reporting of a large number of studies using the phorbol ester family of protein kinase C activators. The ability of protein kinase C activation to open epithelial barriers to a very wide range of solutes is emphasized, but then countered with discussion of the role of phorbol esters and protein kinase C activation in epithelial carcinogenesis. The ability of protein kinase C activation to enable growth factors to leak from luminal fluid compartments of epithelial tissues into lateral intercellular and interstitial fluid spaces may play a role in this carcinogenic action. An examination of protein kinase C effects on the phosphorylation states of tight junctional proteins suggests that downstream kinases and/or phosphatases mediate protein kinase C's effect on tight junction permeability. A role for protein kinase C in transepithelial drug delivery is questioned herein. The tight junctional leakiness associated with protein kinase C activation and apparently intrinsic to transformed epithelia suggests a potentially useful role for tight junction leakiness as a marker for early cancer diagnosis.
Clarke
H
H
Lankenau Medical Research Center, Wynnewood, PA 19096, USA.
Marano
C W
CW
Peralta Soler
A
A
Mullin
J M
JM
D000818:Animals; D003106:Colon / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D062793:Occludin; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D019108:Tight Junctions / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein
D007527:Isoenzymes; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D011493:Protein Kinase C