The potential for signal integration and processing in interacting MAP kinase cascades

Abstract

The cellular response to environmental stimuli requires biochemical information processing through which sensory inputs and cellular status are integrated and translated into appropriate responses by way of interacting networks of enzymes. One such network, the mitogen-activated protein (MAP) kinase cascade is a highly conserved signal transduction module that propagates signals from cell surface receptors to various cytosolic and nuclear targets by way of a phosphorylation cascade. We have investigated the potential for signal processing within a network of interacting feed-forward kinase cascades typified by the MAP kinase cascade. A genetic algorithm was used to search for sets of kinetic parameters demonstrating representative key input-output patterns of interest. We discuss two of the networks identified in our study, one implementing the exclusive-or function (XOR) and another implementing what we refer to as an in-band detector (IBD) or two-sided threshold. These examples confirm the potential for logic and amplitude-dependent signal processing in interacting MAP kinase cascades demonstrating limited cross-talk. Specifically, the XOR function allows the network to respond to either one, but not both signals simultaneously, while the IBD permits the network to respond exclusively to signals within a given range of strength, and to suppress signals below as well as above this range. The solution to the XOR problem is interesting in that it requires only two interacting pathways, crosstalk at only one layer, and no feedback or explicit inhibition. These types of responses are not only biologically relevant but constitute signal processing modules that can be combined to create other logical functions and that, in contrast to amplification, cannot be achieved with a single cascade or with two non-interacting cascades. Our computational results revealed surprising similarities between experimental data describing the JNK/MKK4/MKK7 pathway and the solution for the IBD that evolved from the genetic algorithm. The evolved IBD not only exhibited the required non-monotonic signal strength-response, but also demonstrated transient and sustained responses that properly reflected the input signal strength, dependence on both of the MAPKKs for signaling, phosphorylation site preferences by each of the MAPKKs, and both activation and inhibition resulting from the overexpression of one of the MAPKKs.

Scaffold number in yeast signaling system sets tradeoff between system output and dynamic range

“…Genetic algorithms can often find parameter sets that give good agreement between computed and measured behaviors when others fail, and thus, they are commonly used to optimize parameters in biochemical models (33). Just as important, genetic algorithms can be used to generate multiple, different parameter sets that each result in agreement between computed and measured behaviors (34).…”

Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras–MKK3–p38 to regulate in vitro cellular invasion

“…The involvement of other MAPKs activated by MKK3 is not unlikely considering a cross-talk between the p38, ERK and JNK pathways (Schwacke and Voit, 2007). Moreover, constitutive activation of MKK3 may confer an abnormally strong and sustained signal and thus may activate other MAPK pathways (Qi et al, 2006).…”

“…Signal transduction pathways enable cells to react to a variety of external as well as internal stimuli (Schwacke and Voit, 2007). Perturbation of certain signaling modules by, for example, mutations or aberrant growth factor signaling can induce an unfavorable outcome for the organism, such as tumorigenesis and tumor progression (Ozanne et al, 2007).…”

Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer

“…MAPK family members can also modulate their own signal transduction pathway. This cross-talk occurs at many levels (Cuevas et al, 2007;Han and Sun, 2007;Schwacke and Voit, 2007); there is also feedback inhibition at the mRNA (Ambrosino et al, 2003) and protein levels (Dhillon et al, 2007). For example, 1) p38␣ reduces the stability of mkk6 mRNA (Ambrosino et al, 2003), which is the transcript for one of the p38MAPK kinases, 2) ERK can directly phosphorylate and inhibit Raf1 and son of sevenless (SOS) (a RasGEF and activator of Ras) or indirectly phosphorylate and inhibit SOS via activation of ribosomal s6 kinase 2 (Dhillon et al, 2007), 3) ERK can also inhibit B-Raf and MEK via phosphorylation (Yoon and Seger, 2006), and 4) JNK2 reduces JNK1-mediated phosphorylation of c-Jun (Hochedlinger et al, 2002).…”

“…Knockout mice are available for the various members of the MAPK modules (Gerits et al, 2007), MEKK1-4 connection maps are available (Cuevas et al, 2007), and models of MAPK, MAPKK, and MAPKKK interactions have been designed, revealing the possible level of complexity (Schwacke and Voit, 2007). What we lack is detailed information, a connection map based on subcellular localization, MAPK splice form, cell, development, and stimulus-specific identification of the players involved in signal transduction.…”