Untangling the Web: specific signaling from PKC isoforms to MAPK cascades.

The understanding of intracellular signaling pathways and their physiological effects has been confounded by the existence of numerous isoforms of the various signaling components. Thus, many families of protein kinases comprise several subfamilies, each of which may contain multiple isoforms deriving from distinct genetic loci. Furthermore, each locus may produce multiple products through alternative splicing. A rational argument maintains that each isoform has a distinct role in cellular regulation, but evidence of this is sparse. The alternative explanation, that there is redundancy, has led to the generation of web-like diagrams of interconnecting signaling pathways as investigators attempt to decipher the wiring patterns of the cell. In the heart, two superfamilies of protein kinases, the protein kinase Cs (PKCs) and the mitogen-activated protein kinases (MAPKs), are particularly implicated in the development of cardiac pathologies.1 Both superfamilies contain numerous isoforms, but little is known about the roles of individual isoforms. In this issue of Circulation Research, Heidkamp et al2 provide some of the first data showing that specific PKC isoforms couple to distinct MAPK pathways to regulate cardiac myocyte function.