![]() ![]() These calculations provide insights into one mechanism that describes how the duration of a signal can potentially be regulated in a scaffold mediated protein kinase cascade. Scaffold concentrations that result in optimal signal amplitude also result in the broadest distributions of times over which kinases are activated. Scaffolds can influence the timing of kinase activation by allowing for kinases to become activated over a broad range of times, thus allowing for signaling at both early and late times. The simulations indicate that a major effect that scaffolds exert on the dynamics of cell signaling is to control how the activation of protein kinases is distributed over time. Specifically, we examine the effects of spatially localizing kinase components on a scaffold on signaling dynamics. Here, Monte Carlo simulations of a model kinase cascade are used to investigate how the temporal characteristics of signaling cascades can be influenced by the presence of scaffold proteins. Although scaffolds are widely believed to have dramatic effects on the dynamics of signal propagation, the mechanisms that underlie these consequences are not well understood. Proc Natl Acad Sci U S A 82, 7952–4.Scaffolding proteins that direct the assembly of multiple kinases into a spatially localized signaling complex are often essential for the maintenance of an appropriate biological response. (1985) Complexes of polyoma virus medium T antigen and cellular proteins. (1982) Antibody to the nonapeptide Glu-Glu-Glu-Glu-Tyr-Met-Pro-Met-Glu is specific for polyoma middle T antigen and inhibits in vitro kinase activity. L., Pike, L., Casnellie, J., and Krebs, E. (2007) CK2 Is a component of the KSR1 scaffold complex that contributes to Raf kinase activation. (2003) Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. (2001) C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Muller, J., Ory, S., Copeland, T., Piwnica-Worms, H., and Morrison, D.(2009) Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins. Casar, B., Arozarena, I., Sanz-Moreno, V., Pinto, A., Agudo-Ibanez, L., Marais, R., Lewis, R.(2009) KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals. (1996) KSR modulates signal propagation within the MAPK cascade. (2004) Sef is a spatial regulator for Ras/MAP kinase signaling. Torii, S., Kusakabe, M., Yamamoto, T., Maekawa, M., and Nishida, E.(2004) Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. (2005) IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. (2003) Regulation of MAP kinase signaling modules by scaffold proteins in mammals. (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. (2007) The MEK/ERK cascade: from signaling specificity to diverse functions. ![]()
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