The mitogen-activated protein kinase (MAPK) family consists of both stress activated (SAPK) and mitogen-activated (MAPK) protein kinases. They form a network of signal transduction cascades that mediate cellular responses to a diverse range of stimuli, including growth factors, chemical or osmotic stress, irradiation, bacterial infection and proinflammatory cytokines. Most MAPKs are activated by dual phosphorylation on a Thr-Xaa-Tyr motif by upstream kinases, referred to as MAPK kinases or MKKs. MKKs are, in turn, activated by MKK kinases (MKKKs), over 30 of which have been described. However, the details of how they are activated or which MKKK really activates which MKK in vivo is still poorly understood. MAPK cascades frequently function as multi-protein complexes in which the different components are assembled on a scaffold protein and/or by specific protein-protein docking sites, thereby increasing the speed and specificity of the cascade. Nearly all MAPKs phosphorylate their substrates on serine or threonine residues that precede a proline, but their specificity in vivo is further enhanced by the presence of distinct docking sites that facilitate interaction with substrates.
Fourteen different MAPK family members have been identified in mammalian cells, and homologs are found in all eukaryotic cells. The most studied cascades in mammalian cells are the classical MAPK, p38 (SAPK2) and JNK (SAPK1) cascades. The classical MAPK cascade is activated by mitogens and growth factors, and plays an important role in the control of cell growth and differentiation. However, its inappropriate activation can be a major cause of cell transformation and cancer. It comprises two closely related MAPKs, termed extracellular signal regulated kinase 1 (ERK1) and ERK2. These kinases have many overlapping functions, but mouse knockouts have now revealed that they also have some distinct functions in vivo. Inhibitors which block the activation of MKK1/2 in cells, such as PD 98059, U0126 and PD 184352 and have been used extensively to investigate the functions of the classical MAPK cascade. Moreover, PD 184352 has been shown to strongly suppress the growth of human colon tumors implanted into mice. These three inhibitors were originally thought to be specific for the classical MAPK pathway, but are now known to also block the activation of MKK5, the activator of a distinct MAPK family member ERK5. ERK5 is activated by mitogens and has been suggested to be important for EGF-induced cell proliferation. Mouse knockouts have shown that ERK5 is required for embryonic development and endothelial cell survival.
The JNK cascade is activated by cellular stress, bacterial infection and proinflammatory cytokines, and results in the phosphorylation of AP1 transcription factors, such as c-Jun. There are three related isoforms of JNK each of which gives rise to several splice variants generating a total of ten different JNK variants. Mouse knockouts have shown that JNK1, 2 and 3 have distinct in vivo roles. The p38 cascade is activated by similar stimuli to JNK. Two of the p38 isoforms, α and β are inhibited by a class of anti-inflammatory drugs of which SB-203580 and SB-202190 are examples. These inhibitors have been used to identify many physiological substrates and to implicate the p38 isoforms in diverse cellular processes, including cytokine production and inflammatory responses. More potent p38 inhibitors are currently in clinical trials for the treatment of arthritis. Mouse knockouts have shown p38α is also essential for normal development. Less is known about the other p38 isoforms, γ and δ. P38γ is highly expressed in skeletal muscle, and has been shown to bind to, and co-localize with, α1-syntrophin by virtue of the interaction of its C-terminus with the PDZ domain of α1-syntrophin. P38δ appears to be expressed at low levels in most tissues and little is yet known about its function.
NLK (NEMO like kinase) has been extensively studied in development and can phosphorylate Tcf/Lef proteins and inhibit the DNA-binding ability of β-catenin/Tcf complexes, thereby blocking activation of Wnt targets.
ERK3 and ERK4 and ERK8 are more recently described MAPKs, whose functions are not yet understood. ERK8 appears to be constitutively phosphorylated on its Thr-Xaa-Tyr motif, however its substrates and activators are unknown. ERK3 is unusual in that the Thr-Xaa-Tyr phosphorylation motif is replaced by Ser-Xaa-Glu, and it appears to be rapidly turned over via the proteosome. ERK3 is also implicated in the activation of PRAK.
* Inhibits upstream activator
ERK: Extracellular signal-related kinase
JNK: c-Jun NH(2)-terminal protein kinase
MAPKAP: MAPK-activated protein
MBP: Myelin basic protein
MNK: MAPK-integrating kinase
MSK: Mitogen and stress activated protein kinase
PD 98059: 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
PD 184352: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
PRAK: p38-Regulated activated kinase
RSK: Ribosomal S6 kinase
SAPK: Stress activated protein kinase
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