"Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium.

Mitogen-Activated Protein Kinase Cascades: Terminology and Properties The best-characterized subfamilies of the mitogen-activated protein kinase (MAPK) superfamily are the extracellularly responsive kinases (ERKs) and the two “stress-responsive” MAPK subfamilies, namely, the c-Jun N-terminal kinases (JNKs) and the p38-MAPKs. As yet, no single nomenclature has been determined, and the synonyms currently in use are summarized in Table 1. The ERK cascade is the most thoroughly studied of the MAPK cascades, and it is activated principally by G protein–coupled receptor (GPCR) agonists in cardiac myocytes. We have reviewed this topic recently, and we will not discuss it in any depth here. The regulation of the JNK and p38-MAPK cascades in the myocardium (Figure 1) forms the principal subject of this review. An ever-increasing number of isoforms of MAPKs are being characterized, displaying varying degrees of homology to one another. At least ten JNKs, derived from alternative splicing of three genes, have been identified. The predicted molecular masses of these isoforms are '46 or 54 kDa, depending on the absence or presence of a C-terminal extension, and activities migrating in these positions on SDS-PAGE are clearly detectable in adult rat hearts and in primary cultures of cardiac myocytes prepared from neonatal rat ventricles. It is not clear which of the individual isoforms are present in the myocardium, although a JNK1 antibody immunoprecipitates almost all of the 46-kDa activity and a proportion of the 54-kDa activity. Six p38-MAPK isoforms have been cloned: the alternatively spliced p38MAPK(a1/a2) and p38-MAPKb1/b2 isoforms, p38MAPKg, and p38-MAPKd. The levels of p38-MAPKg and p38-MAPKd transcripts in human heart cDNA libraries are low compared with those of p38-MAPK(a) and p38MAPKb, but it is not yet clear whether these patterns are reflected in the abundances of the proteins. MAPKs are the final components of three-membered protein kinase cascades (Figure 1). They are activated by the dual phosphorylation of a Thr-Xaa-Tyr motif (to PThr-XaaPTyr) catalyzed by dual-specificity MAPK kinases (MKKs), and membership of a given MAPK subfamily can be assigned on the basis of the identity of the Xaa residue (Table 1). Several stress-responsive MKKs (Table 2 and Figure 1) that show some selectivity for specific MAPKs have been identified. The novel MKK, MKK7, is selective for the JNKs, whereas MKK3 and MKK6 activate the p38-MAPKs. MKK4 was first identified as an activator of JNKs but will also stimulate p38-MAPKs. The stress-responsive MKKs are themselves probably phosphorylated and activated by MKK kinases (Figure 1). The MKK kinases (MKKKs) for the JNK and p38-MAPK cascades have not been fully characterized but may include minimally four (or five) MEKKs (for MEK [or ERK] kinase) and other protein kinases. The mechanism of activation of these MKKKs is not clear. As in the ERK cascade, small G proteins of the Ras superfamily (Ras, Rac1, and Cdc42) have been implicated. These may activate protein kinases such as p21-activated kinases and mixed-lineage kinases, which may then activate the JNK and p38MAPK cascades.