MAPKAPK2 (MK2)

MAPKs play central role in mediating the intracellular activity of a variety of extracellular agonists that include growth factors and mitogens. Several groups of MAPK signal transduction pathways have been identified in mammals, including extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAPK. Each of these groups of MAPK is activated by dual phosphorylation on Thr and Tyr within a tripeptide motif (Thr–X–Tyr) located within the activation loop of the MAPK. Downstream targets of these MAPKs are MAPK-activated protein kinases (MKs), which transduce signals to target proteins that are not direct substrates of MAPKs and, therefore, serve to relay phosphorylation-dependent signaling within MAPK cascades to diverse cellular functions. 
One of these groups is formed by the three MKs, MK2, MK3 (also known as 3pK), and MK5 (also designated p38 regulated and activated kinase (PRAK)). While the atypical MAPKs ERK3 and ERK4 mainly activate MK5 the remaining two kinases, MK2 and MK3, are direct substrates of p38 α / β MAPK.  Genome analysis shows that the catalytic domain and C -terminal regulatory part of MK2 are conserved in worms, fruit flies and mammals, whereas the N -terminal prolinerich region is only present in vertebrates. MK2 gets phosphorylated on T222, S272 and T334 by p38 and has a putative autophosphorylation site at T338. MK2 deletion and inhibition studies clearly indicate that catalytic activity of MK2 is required for cytokine production. Thus, structural and catalytic subunits regulate different inflammatory functions of MK2.  MK2 is further classified as MK2 α (372 aa) and MK2 β (400 aa) isoforms. In higher eukaryotic cells, three Cdc25 family members, Cdc25A, Cdc25B and Cdc25C are important substrates of MK2 and these proteins get phosphorylated at Ser/Thr residues by MK2. The ubiquitin ligase human homolog of mouse double minute 2 (HDM2) regulates the function of p53 through degradation and is a direct substrate of MK2. 
MK2 is one of the several downstream substrates of p38, MK2 is therefore a more specific target that acts on limited downstream substrates, thus minimizing its involvement with various mediators.  The major inflammatory functions regulated by MK2 include phosphorylation of various downstream substrates such as heat-shock protein-25/27 (Hsp25/27), tyrosine hydroxylase and leukocyte-specific protein-1 (LSP1).  MK2 is a very crucial enzyme and plays a significant role in a vast array of functions linked with inflammation. The potential efficacy of MK2 inhibitors may thus be greater than would be expected from the inhibition of the mediators alone. MK2 inhibitors are expected to inhibit not only the production of pro-inflammatory cytokines but also their actions, thereby interrupting the vicious cycle that often occurs in inflammatory and immunoresponsive diseases.

References

1.Duraisamy S,et al. Expert Opin Ther Targets. 2008;12(8):921–936.