MAP kinases

Definition
Mitogen activated protein kinases (MAP kinases) is a large kinase network in which upstream kinases activate downstream kinases in response to phosphorylation, translocate to the nucleus and activate different transcription factors.

Discovery
Between 1989 and 1991 the sequences of the first MAP kinase, Kss1p and Fus3p in the pheromone response pathway of the budding yeast and the mammalian MAP kinases ERK1, ERK2 and ERK3, became available, revealing that these enzymes were members of a newly identified protein kinase family1,2. The concept that there were multiple MPKs 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 c-Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPKs), p38 enzymes 3,4.

Structural Characteristics
Catalytic domain- All the MAP kinases share strong amino-acid sequence identity over their catalytic domains (37%-50%), with members of certain subgroups sharing up to 75% identity.

CH2 domains- The amino terminus is much less conserved in the MAP kinases than the catalytic domain. Nevertheless, all MAP kinases contain at their amino terminus two conserved regions that show similarity to the Ccd25 phosphatase, designated CH2 domains.

Docking sites- All MAP kinases have, near to their amino termini, a MAP kinase docking site, which consists of a cluster of positively charged amino acids. It has been proposed that the number of consecutive positively charged residues in this docking site of MAP kinases may play a role in determining binding specificity and therefore catalytic activity

PEST sequences-The subgroup MAP kinases, have an extended carboxyl terminus containing PEST sequences (abundant in proline, glutamate, serine and threonine residues) that are frequently found in rapidly degraded proteins 5.

Mode of Action
MAP kinases are regulated by phosphorylation cascades. Two upstream protein kinases activated in series lead to activation of a MAP kinase, and additional kinases may also be required upstream of this three-kinase module. In all currently known MAP kinase cascades, the kinase immediately upstream of the MAP kinase is a member of the MAP/ERK kinase (MEK or MKK) family. These are dual specificity enzymes that can phosphorylate hydroxyl side chains of serine/threonine and tyrosine residues in their MAP kinase substrates. In spite of their ability to phosphorylate proteins on both aliphatic and aromatic side chains in the appropriate context, the substrate specificity of the known MEKs is very narrow, each MEK phosphorylates only one or a few of the MAP kinase . There are several characteristics of MAP kinases that result from their activation by kinase cascades. Important among these is that the intermediates provide distinct mechanisms for detecting inputs from other signaling pathways to enhance or suppress the signal to the MAP kinase 6.

Functions
One of the best studied signaling routes is the MAP kinase signal transduction pathway and it plays a crucial role in many aspects of immune mediated inflammatory responses. There are several characteristics of MAP kinase that result from their activation by kinase cascades. Important among these is that the intermediates provide distinct mechanisms for detecting inputs from other signaling pathways to enhance or suppress the signal to the MAP kinase. Another is signal amplification, can occur if each successive protein in the cascade is more abundant than its regulator. This may be true at one or both steps within MAP kinase modules. Studies combining over expression and immunoblotting might be interpreted to indicate that each step in the MAP kinase module of the pheromone response pathway in yeast is represented by a successively more abundant protein, so that the signal may be amplified at both steps within the module. In the case of the ERK1/2 pathway, amplification occurs at the Raf-MEK step, because MEK1 is much more abundant (perhaps as high as 1 µM) than Raf, but is not the major function of the MEK-ERK step because the relevant MEKs (MEK1/2) and ERK1/2 are present at approximately the same concentrations. Several MEK family members contain sites that are phosphorylated by kinases in other pathways; these events may influence the ability of MEKs to interact in complexes. Integration may also occur early in the signaling pathway and at the top of the kinase module. Some MEKKs may regulate more than one MAP kinase cascade, and some cascades may be controlled by several, unrelated MEKKs 7.

References
1.Courchesne WE, Kunisawa R, Thorner J (1989). A putative protein kinase overcomes pheromone-induced arrest of cell cycling in S. cerevisiae. Cell., 58:1107–1119.
2.Boulton TG, Yancopoulos GD, Gregory JS, Slaughter C, Moomaw C, Hsu J, Cobb MH (1990). An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science., 249:64–67.
3.Brewster JL, de Valoir T, Dwyer ND, Winter E, Gustin MC (1993). An osmosensing signal transduction pathway in yeast. Science., 259:1760–1763.
4.Lee KS, Irie K, Gotoh Y, Watanabe Y, Araki H, Nishida E, Matsumoto K, Levin DE (1993). A yeast mitogen-activated protein kinase homolog (Mpk1p) mediates signalling by protein kinase C. Mol Cell Biol., 13:3067–3075.
5.Theodosiou A, Ashworth A (2002). MAP kinase phosphatises.Genome Biology., 3(7):1-10.
6.Frost JA, Steen H, Shapiro PS, Lewis R, Ahn J, Shaw PE, Cobb MH (1997). Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO J., 16:6426–6438.
7.Pearson G, Robinson F, Gibson TB, Bing-e Xu, Karandikar M, Berman K, Cobb MH (2001). Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions. Endocrine Reviews., 22 (2):153-183.