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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Bryostatin-1 enhances barrier function in T84 epithelia through PKC-dependent regulation of tight junction proteins

¹Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215; and ²Department of Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio 45267

Submitted 10 June 2002 ; accepted in final form 22 March 2003

Protein kinase C (PKC) is known to regulate epithelial barrier function. However, the effect of specific PKC isozymes, and their mechanism of action, are largely unknown. We determined that the nonphorbol ester PKC agonist bryostatin-1 increased transepithelial electrical resistance (TER), a marker of barrier function, in confluent T84 epithelia. Bryostatin-1, which has been shown to selectively activate PKC-, -, and - (34), was associated with a shift in the subcellular distribution of the tight junction proteins claudin-1 and ZO-2 from a detergent-soluble fraction into a detergent-insoluble fraction. Bryostatin-1 also led to the appearance of a higher-molecular-weight form of occludin previously shown to correspond to protein phosphorylation. These changes were attenuated by the conventional and novel PKC inhibitor Gö-6850 but not the conventional PKC inhibitor Gö-6976 or the PKC- inhibitor röttlerin, implicating a novel isozyme, likely PKC-. The results suggest that enhanced epithelial barrier function induced by bryostatin-1 involves a PKC--dependent signaling pathway leading to recruitment of claudin-1 and ZO-2, and phosphorylation of occludin, into the tight junctional complex.

protein kinase C; epithelial barrier function

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