Abstract

MAPK (Mitogen-activated protein kinase) signalling pathways are characterized by a cascade of multiple kinases that contribute to regulate a variety of extracellular stimuli, thereby to control the cellular environment.

The MAPK family includes the ERKs (extracellular signal-regulated kinase), the JNKs (c-Jun N-terminal kinase), the p38 MAPKs and ERK5. The ERKs generally regulate cellular proliferation and differentiation processes in response to growth factors and other hormones while the JNKs and p38 MAPKs are primarily activated in response to extracellular stresses, such as U.V. irradiation, osmotic stress or inflammatory stimuli (Biondi and Nebreda, 2003).

MAPKs are serine/threonine kinases that tend to phosphorylate their substrates on S/T-P motif. As the sequence S/T-P is found in ~ 80% of all proteins additional factors are required to direct individual kinases towards the correct substrates (Bardwell, 2006). One way by which the MAPKs ensure their substrate specificity is by interaction through docking motifs, short amino acid stretches located on MAPK-interacting proteins.

The classical docking motif is characterized by a cluster of at least two positively charged amino acids followed by by a spacer of 2-to-6 residues from a hydrophobic-X-hydrophobic sequence, where the hydrophobic residues are long-chain aliphatics (usually Leu, Ile). Both in the spacer and in the sequence immediately C-terminal to the hydrophobic-X-hydrophobic element, there is a high propensity for the presence of Pro, Asn, and/or Gly, which are residues that are both turn-forming and helix-breaking (Bardwell, 2000).

Another type of docking motif is a short peptide containing the sequence FXFP that is usually downstream of the phosphorylation site. This motif was originally found to bind the ERK subfamily but lately it has been shown to promote the interaction with p38alpha and p38 beta2 (Jacobs et al., 1999; Galanis el at., 2001).

Substrates can contain the classical docking motif or the FXFP or often contain both. (Sharrocks et al., 2000).