There are, of course, exceptions to the above statement, and one of the most prominent of these is combinatorial inhibition, a phenomenon similar to the prozone effect observed in immune response, in which excess scaffold concentration inhibits response to signal ( 9). Nonetheless, many of these ideas (particularly the concept that scaffolds limit or prevent signal amplification) have become widely accepted within the field ( 3, 4). Despite the fact that scaffold proteins have been the subject of numerous theoretical and experimental studies ( 7- 10), surprisingly few of these hypotheses have ever been explored in a rigorous way. Others have speculated that scaffolds serve to prevent unwanted crosstalk between pathways, by sequestering kinases that are shared by two cascades onto a physical platform specific to one of them ( 5, 6). For instance, many have argued that scaffolds prevent signal amplification, based on the intuition that stoichiometric limitations imposed by the scaffold should limit activation of downstream species ( 3, 4). While scaffolds are common, there are clear examples of kinase cascades that function without them ( 1) this has led to a wide array of hypotheses regarding the functional role scaffolds play in the cascades in which they are found ( 3, 4). Interestingly, many of these cascades involve a dedicated “scaffold protein,” which often have no catalytic activity themselves, but rather serve as a multivalent nucleation point for the assembly of signaling complexes ( 1, 3, 4). Intracellular signaling networks form the basis for cellular adaptation to the environment, and kinase cascades are a common motif in these networks, particularly in eukaryotes ( 1, 2). Our findings should also inform attempts to target scaffold proteins for therapeutic intervention and the design of scaffolds for synthetic biology. In addition to providing novel insights into the function of scaffold proteins, our work suggests experiments that could distinguish between assembly paradigms. We found that several well-accepted hypotheses regarding the role of scaffolds in regulating signal response either do not hold or depend critically on the assembly paradigm employed. We considered two paradigms of scaffold assembly: as either the nucleation point for assembly of discrete multi-subunit proteins (the machine paradigm) or a platform upon which kinases independently associate (the ensemble paradigm). Here, we used dynamical models of scaffold signaling to investigate the impact scaffolds have on network behavior. While scaffolds play a fundamental role in regulating signaling, few hypotheses regarding their function have been rigorously examined. Many signaling networks involve scaffold proteins that bind multiple kinases in kinase cascades.
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