Daria Mochly-Rosen

Research/Lab website:   Mochly-Rosen Lab Site

We are studying the mechanism of protein kinase C-mediated signal transduction in several disease models. Based on our recent data, we proposed a working hypothesis that activated PKC isozymes bind to intracellular receptor proteins located at different subcellular sites, and that these receptors differentially bind specific PKC isozymes. Evidence was obtained for the presence of intracellular receptor proteins that bind activated PKC. Binding of PKC to these proteins was concentration-dependent, saturable and specific, suggesting that these binding proteins are receptors for activated C-kinase, or "RACKs".

We have characterized and cloned several RACKs and identified domains in different PKC isozymes that are required for the specific association with these RACKs; these domains are distinct from the substrate binding site on PKC. On the basis of this information, together with computer modeling of crystal structures of the interacting proteins, we have identified novel isozyme-selective inhibitors that inhibit translocation and the consequent function of individual PKC isozymes. These inhibitors are fragments of PKC or RACKs that have 'dominant negative' activities on PKC binding to RACKs and on their activities, in vivo. In addition, we prepared synthetic peptides corresponding to the binding sites in PKC and RACKs. We are currently determining the effects of these isozyme-selective translocation inhibitors on a number of PKC-mediated cell functions in normal and diseased heart. These include cardiac and smooth muscle cell contraction, gene expression, hypertrophy, and response to and protection from ischemic insult.