Cells coordinate and integrate various functional modules that control their dynamics, intracellular trafficking, metabolism and gene expression. Such capacity is mediated by specific scaffold proteins that tether multiple components of signaling pathways at plasma membrane, Golgi apparatus, mitochondria, endoplasmic reticulum, nucleus and in more specialized subcellular structures such as focal adhesions, cell-cell junctions, endosomes, vesicles and synapses. Scaffold proteins act as "pacemakers" as well as "placemakers" that regulate the temporal, spatial and kinetic aspects of protein complex assembly by modulating the local concentrations, proximity, subcellular dispositions and biochemical properties of the target proteins through the intricate use of their modular protein domains. These regulatory mechanisms allow them to gate the specificity, integration and crosstalk of different signaling modules. In addition to acting as physical platforms for protein assembly, many professional scaffold proteins can also directly modify the properties of their targets while they themselves can be regulated by post-translational modifications and/or mechanical forces. Furthermore, multiple scaffold proteins can form alliances of higher-order regulatory networks. Here, we highlight the emerging themes of scaffold proteins by analyzing their common and distinctive mechanisms of action and regulation, which underlie their functional plasticity in cell signaling. Understanding these mechanisms in the context of space, time and force should have ramifications for human physiology and for developing new therapeutic approaches to control pathological states and diseases.
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