© 2001 American Heart Association, Inc.
Editorials |
Untangling the Web
Specific Signaling From PKC Isoforms to MAPK Cascades
From the Division of Biomedical Sciences (Cell and Molecular Biology Section) (A.C.) and the National Heart and Lung Institute Division (Cardiac Medicine Section) (P.H.S.), Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.
Correspondence to Angela Clerk, PhD, Division of Biomedical Sciences (Cell and Molecular Biology Section), Faculty of Medicine, Imperial College of Science, Technology and Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK. E-mail a.clerk@ic.ac.uk
See related article, pages 882–890
Key Words: cardiac myocytes • protein kinase C • mitogen-activated protein kinases • hypertrophy • apoptosis
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.
PKC and the MAPKs
The PKC superfamily comprises the "classical" cPKCs (
, ß1, ß2, 
), "novel" nPKCs (
, 
, 
, 
), "atypical" aPKCs (
, 
/
), and PKC-related kinases (PRKs).3 In cardiac myocytes, cPKC, nPKC, nPKC, aPKC, and aPKC/ are readily detectable, although cPKCß isoforms may also be significant.4 Hypertrophic agonists such as endothelin-1 (ET-1) or the -adrenergic agonist phenylephrine (PE) activate nPKC and nPKC in cardiac
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