Scaffold protein in cascades11/8/2023 ![]() ![]() 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). 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. The proteins that act as scaffolds include KSR1/2, IQGAP1, β-arrestin 1/2, MORG1, MP1, and paxillin in mammalian systems. These scaffolds bring together and organize components of the cascade to facilitate MAPK activation. ![]() Scaffold proteins are defined by the binding of at least two members of a signaling cascade ( Chuderland and Seger, 2005 Oda et al., 2005). However, in recent years it became clear that a number of scaffold proteins play an essential role in the regulation of this signaling network. 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). A diverse range of receptors initiates this pathway, which consists of a phosphorylation-dependent relay of protein activation, resulting in altered transcription, ultimately regulating processes such as cell proliferation and differentiation. 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. Thus, more realistic models are needed to understand the role of scaffolds in mammalian signal transduction, which opens a big opportunity for systems biology. ![]() 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. For scaffolds in mammalian signaling, however, models have been rather generic and sketchy. For the yeast scaffold Ste5, detailed mechanistic models have been valuable for the understanding of its function. 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. 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. Scaffolding proteins add a new layer of complexity to the dynamics of cell signaling. 3Manchester Institute of Biotechnology, University of Manchester, Manchester, UK.2Institute for Theoretical Biology, Humboldt University Berlin, Berlin, Germany.1Institute of Pathology, Charité–Universitätsmedizin Berlin, Berlin, Germany.Franziska Witzel 1,2† Louise Maddison 3† Nils Blüthgen 1,2* ![]()
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