Mitogen-Activated Protein Kinase (MAPK) Signalling Pathways

Overview & Structure

A protein kinase is an enzyme that can transfer a phosphate group from a donor molecule (usually ATP) to an amino acid residue of a protein. The protein kinase mechanism is used in signal transduction for the regulation of enzymes. Phosphorylation can activate (or inhibit) the activity of an enzyme. Mitogen-activated protein kinases (MAPK) are members of a conserved cascade of kinases involved in many signal transduction pathways. They stimulate phosphorylation of transcription factors in response to extracellular signals such as growth factors, cytokines, ultraviolet light, and stress-inducing agents.

The MAP kinases, also referred to as extracellular signal-regulated protein kinases, or ERKs, are the terminal enzymes in a three-kinase cascade. Several MAPK cascades have been identified in mammalian cells. The recent identification of distinct MAPK cascades that are conserved across all eukaryotes indicates that the MAPK module has been adapted for interpretation of a diverse array of extracellular signals.

The activities of ERK1 and ERK2 had been routinely measured with two substrates, myelin basic protein (MBP) and microtubule-associated protein-2 (MAP2); as a result, they had been called MBP and MAP2 kinases. The MAP acronym is still used, but with a different meaning. The name mitogen-activated protein kinase was assigned to these enzymes to acknowledge the fact that they had first been detected as mitogen-stimulated tyrosine phosphoproteins in the early 1980s. The concept that there were multiple MAP kinases with distinct regulation and functions arose from the description of additional pathways found initially in yeast, the high osmolarity glycerol (HOG) pathway containing the MAP kinase HOG1 and the cell wall pathway containing the kinase MPK1, and then in metazoans with the discovery of c-Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPKs), p38 enzymes, and others.

Although mitogen activation of the MAPK subfamilies ERK1 and ERK2 has dominated efforts to understand MAPK signaling, more studies are now focusing on the role of the stress-activated kinases, paricularlyp38 and JNK. This illustrates the diverse nature of the MAPK superfamily of enzymes (Figure 1). And although sequence similarities among components of the individual MAPK modules used for activation of ERK1/2, JNKs and p38 are considerable, the fidelity that is maintained in order to translate specific extracellular signals into physiological responses illustrates the selective adaptation of each MAPK module. Understanding how such specificity is maintained, and the extent and significance of cross-talk between each signaling cascade, are fundamental issues that are actively being investigated by researchers.

All MAPK pathways operate through sequential phosphorylation events to phosphorylate transcription factors and regulate gene expression. They can also phosphorylate cytosolic targets to regulate intracellular events. MAPKs are phosphorylated and activated by MAPK kinases (MKKs), which in turn are phosphorylated and activated by MKK kinases (Raf and MKKK). The final goal of these cascades is the regulation of cellular proliferation, differentiation, development, cell cycle, and transmission of oncogenic signals through gene transcription.

Different structures of MAP Kinases:

Figure 1. ERK1

(5)

Figure 2. ERK2

Here the peptide binding site is blocked by tyrosine 185, one of the two residues that are phosphorylated in the active enzyme. Activation of ERK2 thus is likely to involve both global and local conformational changes.

Figure 3. p38 structure

(6)

Fig. 4 p38 MAP kinase with inhibitor

Fig 5. Structure of C-Jun N-terminal kinase (JNK3S)

complexed with Mg2+ AMPPNP.

Fig 6. MAP Kinase Pathways

References:

1) www.mergen.com/genecat.asp?cat=MAPK

2) http://en.wikipedia.org/wiki/Protein_kinase

3)http://www.sigmaaldrich.com/Area_of_Interest/Life_Science/Cell_Signaling/Scientific_Resources/Pathway_Slides___Charts/Mitogen_activated_Protein_Kinase_Cascades.html

4) http://edrv.endojournals.org/cgi/content/full/22/2/153

5) http://pkr.sdsc.edu/html/3D/text/1erk/1erk.html

6) http://pkr.sdsc.edu/html/3D/text/1p38/1p38.html

7) http://www.promega.com/pnotes/59/5644f/5644f_core.pdf

8) http://www.biocarta.com/pathfiles/h_mapkPathway.asp