The family of mitogen-activated protein kinases (MAPKs) comprises several protein kinases, united by their ability to phosphorylate serine or threonine residues followed by proline; therefore, these often are termed proline-directed protein kinases. Another characteristic feature of the MAPKs is the presence of specific phosphoacceptor site(s) in the regulatory loop of the enzyme catalytic core.

HISTORY AND EVOLUTION

MAPKs were originally named after the protein they were discovered to phosphorylate in insulin- or growth factor–treated mammalian cells, namely microtubule-associated protein 2 (MAP-2). Later, with the realization that virtually all mitogens lead to the rapid activation of these protein kinases, the enzymes were renamed mitogen-activated protein kinases. Now, it is clear that MAPK function is not limited to the initially described induction of cell division, but also extends to control over cell differentiation, survival, motility, and gene expression. Because MAPKs orchestrate the physiological processes fundamental for both single- and multicellular organisms, it is not surprising that homologous enzymes are found in eukaryotes from budding yeast to mammals (1). The deletion of certain MAPK genes in mammals leads to early embryonic lethality, proving the essential role of MAPK signaling in the developmental processes (Table 81–1).

MITOGEN-ACTIVATED PROTEIN KINASE STRUCTURE AND FUNCTION

To date, five different groups of MAPKs are known in mammals. Enzymes within groups are generated from a number of gene products; additional isoforms were shown to derive from the alternative splicing of pre-mRNAs (12). Mammalian MAPKs include extracellular-signal-regulated protein kinase (ERK)1/2; p38 MAPKs (α, β, γ, and δ); c-jun N-terminal kinases (JNK1, JNK2, JNK3);ERK5, also known as BMK1(13); and the recently identified ERK3 subfamily, comprising the products of two genes, MAPK4 and MAPK6 (14).