Abstract
Scaffolding proteins add a new layer of complexity to the dynamics of cell signaling. Above their basic function to bring several components of a signaling pathway together, recent experimental research has found that scaffolds influence signaling in a much more complex way: scaffolds can exert some catalytic function, influence signaling by allosteric mechanisms, are feedback-regulated, localize signaling activity to distinct regions of the cell or increase pathway fidelity. Here we review experimental and theoretical approaches that address the function of two MAPK scaffolds, Ste5, a scaffold of the yeast mating pathway and KSR1/2, a scaffold of the classical mammalian MAPK signaling pathway. For the yeast scaffold Ste5, detailed mechanistic models have been valuable for the understanding of its function. For scaffolds in mammalian signaling, however, models have been rather generic and sketchy. For example, these models predicted narrow optimal scaffold concentrations, but when revisiting these models by assuming typical concentrations, rather a range of scaffold levels optimally supports signaling. Thus, more realistic models are needed to understand the role of scaffolds in mammalian signal transduction, which opens a big opportunity for systems biology.
Highlights
The three-tiered MAPK signaling cascade is a highly conserved signaling pathway that regulates the cellular response to a variety of external stimuli in all eukaryotes
While more and more mechanistic details about the action of scaffolds emerge, the role for scaffolds on the dynamics of MAPK signaling is currently not well-established for mammalian cells
Detailed mechanistic mathematical modeling and quantitative experimentation has been useful in the past by shedding light on how signaling works dynamically
Summary
The three-tiered MAPK signaling cascade is a highly conserved signaling pathway that regulates the cellular response to a variety of external stimuli in all eukaryotes. A diverse range of receptors initiates this pathway, which consists of a phosphorylation-dependent relay of protein activation, resulting in altered transcription, regulating processes such as cell proliferation and differentiation The details of this signaling pathway are very well studied and detailed maps of the function of specific protein kinases and protein phosphatases within the pathway have been produced (Oda et al, 2005). While most systems-biological research into the pathway neglected the presence of the scaffolds, in recent years many detailed mechanistic studies have been conducted that shed light on the function of these proteins Besides their main function of assembling complexes, scaffolds are thought to minimize crosstalk with other signaling cascades (Dhanasekaran et al, 2007) and likewise mediate crosstalk (Kolch, 2005), protect kinases from phosphatases (Perlson et al, 2006) and target signals to a specific subcellular location (Roskoski, 2012). KSR, Kinase Suppressor of Ras, was originally identified as a regulator of Ras following genetic screens in D. melanogaster and C. elegans www.frontiersin.org
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