MAP kinase pathways: The first twenty years

Abstract

The MAP kinases, discovered approximately 20 years ago, together with their immediate upstream regulators, are among the most highly studied signal transduction molecules. This body of work has shaped many aspects of our present views of signal transduction by protein kinases. The effort expended in this area reflects the extensive participation of these regulatory modules in the control of cell fate decisions, i.e., proliferation, differentiation and death, across all eukaryotic phylla and in all tissues of metazoans. The discovery of these kinases is reviewed, followed by a discussion of some of the features of this signaling module that account for its broad impact on cell function and its enormous interest to many investigators.

Calcium-mediated Interactions Regulate the Subcellular Localization of Extracellular Signal-regulated Kinases

“…The ERK 3 cascade, which is a central and ubiquitous signaling pathway, utilizes Raf kinases MEKs and ERKs as its kinase components (1)(2)(3). Three isoforms of ERKs are currently known, ERK1, ERK2, and ERK1b/c (4 -6), which upon extracellular stimulation are activated by MEK1 and MEK2.…”

SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress

“…Thus, PLK4 protects cells from apoptosis by mediating stressinduced AKT activation. Based on the combined findings, we conclude that stress stimuli activate SAPKKKs, which then activate both pro-survival PLK4 and pro-apoptotic SAPK signalling 24,41,42 . At the same time, stress stimuli induce p53 that suppresses PLK4 expression.…”

“…For instance, several SAPKKKs phosphorylate inhibitor of nuclear factor k-B kinase b (IKKb) in addition to their cognate SAPKKs 24 . Here we showed that PLK4 is a novel substrate of several SAPKKKs.…”

“…Activated p53 interacts with sequencespecific DNA-binding sites and modulates, either positively or negatively, the expression of its target genes, thereby potentiating apoptosis. Another prominent event that responds rapidly to stress conditions is activation of the stress-activated p38 and JNK MAPK (SAPK) cascades 24,25 . The SAPK cascades consist of a three-tiered core of protein kinases, namely SAPKKK, SAPK kinase (SAPKK) and SAPK, and are activated by various stresses (for example, DNA damage, osmotic stress or oxidative stress) and by inflammatory cytokines (for example, tumour-necrosis factor-a (TNFa) or interleukin-1).…”

Mutual Regulation of Receptor-Mediated Cell Signalling and Endocytosis: EGF Receptor System as an Example

“…Activated ERK may also translocate into the nucleus to activate transcription factors such as Elk1 and c-fos, which is critical in controlling cell mitogenesis (Fig. 3B) [2,24,[30][31][32][33][34].…”