Key Points
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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.
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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.
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Initial studies of scaffold proteins indicate that they are important for spatial localization and amplification of signal transduction.
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Scaffolds can generate complex behaviours that include transient or sustained signalling, and oscillatory signalling, as well as provide positive and negative feedback.
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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.
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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.
Abstract
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.
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FURTHER INFORMATION
Glossary
- Immunological synapse
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A large junctional structure that is formed at the cell surface between a T cell that is interacting with an APC or a target cell, which consists of molecules that are required for adhesion and signalling. This structure is important for establishing T-cell adhesion and polarity, is influenced by the cytoskeleton and transduces highly controlled secretory signals, thereby allowing the directed release of cytokines or lytic granules towards the APC or target cell.
- 14-3-3 proteins
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A family of conserved proteins that is present in all eukaryotic organisms and is involved in diverse cellular processes, such as apoptosis and stress, as well as intracellular signalling and cell-cycle regulation. 14-3-3 proteins function as scaffolds in protein interactions and can regulate protein localization and enzymatic activity. Approximately 100 binding partners for the 14-3-3 proteins have been reported.
- Caspase-recruitment domain
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A domain that is found in certain initiator caspases (for example, mammalian caspase 9) and their adaptor proteins (for example, APAF1). This domain mediates protein–protein interactions.
- Nuclear export signal
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A short amino-acid sequence of 5–6 hydrophobic residues that targets a protein for export from the cell nucleus to the cytoplasm.
- Leucine zipper
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A common dimerization domain found in some proteins that are involved in regulating gene expression. Leucine zipper refers to the secondary structure of two parallel α-helices found in the protein.
- Effector memory T cell
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A terminally differentiated T cell that lacks lymph-node-homing receptors but expresses receptors that enable it to home to inflamed tissues. Effector memory cells can exert immediate effector functions without the need for further differentiation.
- Inflammasome
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A molecular complex of several proteins that, once assembled, cleaves pro-IL-1β, thereby producing active IL-1β.
- Vitiligo
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A depigmenting disorder of the skin caused by the destruction of melanocytes, which produce cutaneous pigments.
- Short hairpin RNA
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One of the two most common forms of short (∼21 base pairs) double-stranded RNAs that are used for gene silencing. The other form is small interfering RNA.
- Uropod
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The posterior tail of migrating amoeboid cells. It is rich in filamentous actin, microtubules and cytoskeletal adaptor proteins (such as ezrin and moesin), as well as adhesion molecules (such as CD43 and CD44) and lipid rafts.
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Shaw, A., Filbert, E. Scaffold proteins and immune-cell signalling. Nat Rev Immunol 9, 47–56 (2009). https://doi.org/10.1038/nri2473
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DOI: https://doi.org/10.1038/nri2473