Scaffold proteins and immune-cell signalling

Key Points Scaffold proteins have an important role in regulating immune-cell signalling. This Review provides an overview of the numerous functions that have been attributed to scaffold proteins, and discusses various cytoplasmic scaffold proteins that are important in immune cells. Although little is known about the exact role of scaffold proteins, mathematical modelling and engineered scaffold proteins have greatly enhanced our knowledge of their function. Initial studies of scaffold proteins indicate that they are important for spatial localization and amplification of signal transduction. Scaffolds can generate complex behaviours that include transient or sustained signalling, and oscillatory signalling, as well as provide positive and negative feedback. In immune cells, scaffold proteins have an important role in the regulation of mitogen-activated protein kinase activation, calcium signalling, signalling downstream of innate immune receptors and cell polarity. The function and regulation of scaffold proteins is complex and much remains to be defined. It is probable that new tools, in addition to classic biochemical approaches, will be required to elucidate these functions. Scaffold proteins are known to have an important role in signal transduction but their mechanisms of activation are still unclear. In this Review, recent studies that have shed light on the function of cytoplasmic scaffold proteins in immune-cell signalling are discussed. Over the past 20 years great progress has been made in defining most of the key signalling pathways that functionally regulate immune cells. Recently, it has become clear that scaffold proteins have a crucial role in regulating many of these signalling cascades. By binding two or more components of a signalling pathway, scaffold proteins can help to localize signalling molecules to a specific part of the cell or to enhance the efficacy of a signalling pathway. Scaffold proteins can also affect the thresholds and the dynamics of signalling reactions by coordinating positive and negative feedback signals. In this Review, we focus on recent progress in the understanding of the function of scaffold proteins in immune cells.