Abstract
Signaling through mitogen-activated protein kinase (MAPK) cascades is a conserved and fundamental process in all eukaryotes. This chapter reviews recent progress made in the identification of components of MAPK signaling networks using novel large scale experimental methods. It also presents recent landmarks in the computational modeling and simulation of the dynamics of MAPK signaling modules. The in vitro MAPK signaling network reconstructed from predicted phosphorylation events is dense, supporting the hypothesis of a combinatorial control of transcription through selective phosphorylation of sets of transcription factors. Despite the fact that additional co-factors and scaffold proteins may regulate the dynamics of signal transduction in vivo, the complexity of MAPK signaling networks supports a new model that departs significantly from that of the classical definition of a MAPK cascade.
TopIntroduction
Mitogen-activated protein kinase (MAPK) cascades are components of intracellular signaling activated in response to a wide array of external and internal signals, contributing towards development of diverse cellular responses such as growth, differentiation, response to pathogens, and cell death. A MAPK cascade contains several key components: a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K) and a MAPK. MAP3Ks, activated by upstream kinases or receptor-associated molecules, activate in turn the MAP2Ks. Activated MAP2Ks phosphorylate the MAPK components which, in turn, phosphorylate diverse substrates such as transcription and translation factors, protein kinases and phosphatases, thus regulating many cellular processes in response to the initial stimulus (Chen & Thorner, 2007; Zhang et al., 2006).
In plants, the diversity of processes regulated through MAPK signaling cascades combined with the large number of predicted members within MAPK families implies a robust and well synchronized control of kinase signaling. In support of this hypothesis, recent large-scale screens to identify signaling proteins in eukaryotic organisms challenged the classical view of signaling cascades as simple, linear conduits composed of a handful of elements. Current models reflect the apparent complexity of signaling pathways, the cross-talk between parallel pathways, and the dynamic nature of the protein interactions (Friedman & Perrimon, 2006, 2007; Mackay, 2004; Popescu et al., 2007). A recent study (Popescu, Popescu, & Bachan et al., 2009) re-constituted a MAPK phosphorylation network based on experimental data generated using high-density protein microarrays. The study found that MAPKs are able to phosphorylate in vitro a large diversity of transcription factors with known or predicted roles in disease resistance, flower development, cellular differentiation and auxin signaling. The analysis of the re-constituted signaling network supported the hypothesis of a combinatorial control of cellular processes through MAP2Ks and MAPKs cascades.
In this chapter, we present a systems view of the molecular interactions of the MAPK proteins and review current results on the architecture and dynamics of MAPK signaling networks.
Key Terms in this Chapter
Protein Phosphorylation: An enzymatic reaction consisting in addition of a phosphate group to specific residues of a protein.
Protein Interaction Network: A network representation of protein-protein interactions in a cell.
Mitogen Activated Protein Kinases (MAPK): A class of kinase proteins that are phosphorylated upon stimulation by an extracellular stimulus (signal) and participate in the transduction of this signal.
Kinome: The set of protein kinase genes within the genome of an organism.
MAPK Signaling Network: A network composed of MAPK signaling pathways, including MAP3Ks, MAP2Ks, MAPKs and their phosphorylation targets.
Michaelis-Menten Kinetics: An equation describing steady state dynamics of enzymatic reactions.