p38 MAP kinases: beyond the stress response

Many extracellular stimuli are converted into specific cellular responses through the activation of mitogen-activated protein kinase (MAPK) signalling pathways. MAPKs are serine/threonine protein kinases that can phosphorylate both cytoplasmic and nuclear targets. Consistent with their name, the founder members of the MAPK family [p42/p44 extracellular signal-regulated kinases (ERKs)] are predominantly activated by mitogenic stimuli. However, other MAPK family members have been identified that are preferentially activated by non-mitogenic stimuli; these include the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 MAPK subfamilies, which are activated by most environmental stresses. The p38 MAPKs are also strongly activated by pro-inflammatory cytokines such as interleukin 1 (IL-1) and tumour necrosis factor α (TNF-α), which play an important role in the regulation of the inflammatory response. This potential therapeutic value, together with the availability of chemical inhibitors (e.g. SB203580), which preferentially target the p38α and p38β MAPKs (Fig. 1), has made these protein kinases the subject of intensive studies during the past years. Four isoforms of p38 MAPKs (p38α, β, γ and δ, also known as SAPK2a, 2b, 3 and 4, respectively) have been identified, which are all phosphorylated and activated by the MAPK kinase MKK6 [also known as SKK3 (for SAPK kinase)]. Other MKKs show more restricted specificity, for example, MKK3 activates p38α, p38γ and p38δ, whereas MKK4 can only activate p38α. Substrates of p38 MAPKs include mainly other protein kinases and a growing list of transcription factors (Fig. 1). Here, we discuss recent reports demonstrating a previously unsuspected role for p38 MAPKs in a number of cellular functions unrelated to stress responses. These include the developmental processes of oogenesis and wing morphogenesis in flies, as well as differentiation, proliferation and survival in several vertebrate cell types (Fig. 2). Figure 2Cellular processes regulated by p38 mitogen-activated protein kinases (MAPKs). The involvement of p38 in inflammation, apoptosis and the stress response has been well documented. Recent data are summarized that connect p38 activation with various processes of differentiation, proliferation and survival, as well as Drosophila development. View Large Image Figure Viewer