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  • Review Article
  • Published:

Scaffold proteins and immune-cell signalling

Nature Reviews Immunology volume 9, pages 47–56 (2009)Cite this article

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.

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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Figure 1: The function of scaffold proteins.
Figure 2: Mitogen-activated protein kinase scaffold proteins in immune signalling.
Figure 3: Scaffold proteins of the calcium signalling pathway.
Figure 4: DLG1 in T cells.

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References

  1. Cooper, J. A., Bowen-Pope, D. F., Raines, E., Ross, R. & Hunter, T. Similar effects of platelet-derived growth factor and epidermal growth factor on the phosphorylation of tyrosine in cellular proteins. Cell 31, 263–273 (1982).

    Article  CAS  PubMed  Google Scholar 

  2. Wang, Y., Pennock, S., Chen, X. & Wang, Z. Internalization of inactive EGF receptor into endosomes and the subsequent activation of endosome-associated EGF receptors. Epidermal growth factor. Sci. STKE 2002, PL17 (2002).

    PubMed  Google Scholar 

  3. Wang, Y., Pennock, S. D., Chen, X., Kazlauskas, A. & Wang, Z. Platelet-derived growth factor receptor-mediated signal transduction from endosomes. J. Biol. Chem. 279, 8038–8046 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Kane, L. P., Lin, J. & Weiss, A. Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12, 242–249 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Aggarwal, B. B. Signalling pathways of the TNF superfamily: a double-edged sword. Nature Rev. Immunol. 3, 745–756 (2003).

    Article  CAS  Google Scholar 

  7. Aguado, E., Martinez-Florensa, M. & Aparicio, P. Activation of T lymphocytes and the role of the adapter LAT. Transpl. Immunol. 17, 23–26 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Wu, J. N. & Koretzky, G. A. The SLP-76 family of adapter proteins. Semin. Immunol. 16, 379–393 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Burack, W. R., Cheng, A. M. & Shaw, A. S. Scaffolds, adaptors and linkers of TCR signaling: theory and practice. Curr. Opin. Immunol. 14, 312–316 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Nakanishi, H. et al. Neurabin: a novel neural tissue-specific actin filament-binding protein involved in neurite formation. J. Cell Biol. 139, 951–961 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Levchenko, A., Bruck, J. & Sternberg, P. W. Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. Proc. Natl Acad. Sci. USA 97, 5818–5823 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ferrell, J. E. Jr. What do scaffold proteins really do? Sci. STKE 2000, PE1 (2000).

    Article  PubMed  Google Scholar 

  13. Burack, W. R. & Shaw, A. S. Signal transduction: hanging on a scaffold. Curr. Opin. Cell Biol. 12, 211–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Wong, W. & Scott, J. D. AKAP signalling complexes: focal points in space and time. Nature Rev. Mol. Cell Biol. 5, 959–970 (2004).

    Article  CAS  Google Scholar 

  15. Williams, R. O. Cutting Edge: A-kinase anchor proteins are involved in maintaining resting T cells in an inactive state. J. Immunol. 168, 5392–5396 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Locasale, J. W., Shaw, A. S. & Chakraborty, A. K. Scaffold proteins confer diverse regulatory properties to protein kinase cascades. Proc. Natl Acad. Sci. USA 104, 13307–13312 (2007). This study uses mathematical modelling to examine possible functions of scaffold proteins and identifies important variables that might alter these functions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pincet, F. Membrane recruitment of scaffold proteins drives specific signaling. PLoS ONE 2, e977 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Uhlik, M. T., Abell, A. N., Cuevas, B. D., Nakamura, K. & Johnson, G. L. Wiring diagrams of MAPK regulation by MEKK1, 2, and 3. Biochem. Cell Biol. 82, 658–663 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Bashor, C. J., Helman, N. C., Yan, S. & Lim, W. A. Using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics. Science 319, 1539–1543 (2008). Using engineered scaffold proteins to recruit pathway modulators to a signalling cascade, this study identifies a range of signalling behaviours that can be induced by scaffold proteins.

    Article  CAS  PubMed  Google Scholar 

  20. Park, S. H., Zarrinpar, A. & Lim, W. A. Rewiring MAP kinase pathways using alternative scaffold assembly mechanisms. Science 299, 1061–1064 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Dueber, J. E., Mirsky, E. A. & Lim, W. A. Engineering synthetic signaling proteins with ultrasensitive input/output control. Nature Biotechnol. 25, 660–662 (2007).

    Article  CAS  Google Scholar 

  22. Lewis, R. S. Calcium signaling mechanisms in T lymphocytes. Annu. Rev. Immunol. 19, 497–521 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Kolch, W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nature Rev. Mol. Cell Biol. 6, 827–837 (2005).

    Article  CAS  Google Scholar 

  24. Elion, E. A. The Ste5p scaffold. J. Cell Sci. 114, 3967–3978 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Claperon, A. & Therrien, M. KSR and CNK: two scaffolds regulating RAS-mediated RAF activation. Oncogene 26, 3143–3158 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Therrien, M. et al. KSR, a novel protein kinase required for RAS signal transduction. Cell 83, 879–888 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Kornfeld, K., Hom, D. B. & Horvitz, H. R. The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell 83, 903–913 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Sundaram, M. & Han, M. The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 83, 889–901 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Cacace, A. M. et al. Identification of constitutive and Ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. Mol. Cell. Biol. 19, 229–240 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Muller, J., Ory, S., Copeland, T., Piwnica-Worms, H. & Morrison, D. K. C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol. Cell 8, 983–993 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Douziech, M., Sahmi, M., Laberge, G. & Therrien, M. A KSR/CNK complex mediated by HYP, a novel SAM domain-containing protein, regulates RAS-dependent RAF activation in Drosophila. Genes Dev. 20, 807–819 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Therrien, M., Wong, A. M. & Rubin, G. M. CNK, a RAF-binding multidomain protein required for RAS signaling. Cell 95, 343–353 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Boudeau, J., Miranda-Saavedra, D., Barton, G. J. & Alessi, D. R. Emerging roles of pseudokinases. Trends Cell Biol. 16, 443–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Huang, C. L., Cha, S. K., Wang, H. R., Xie, J. & Cobb, M. H. WNKs: protein kinases with a unique kinase domain. Exp. Mol. Med. 39, 565–573 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Mukherjee, K. et al. CASK functions as a Mg2+– independent neurexin kinase. Cell 133, 328–339 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ohmachi, M. et al. C. elegans ksr-1 and ksr-2 have both unique and redundant functions and are required for MPK-1 ERK phosphorylation. Curr. Biol. 12, 427–433 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Channavajhala, P. L. et al. Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling. J. Biol. Chem. 278, 47089–47097 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Nguyen, A. et al. Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol. Cell. Biol. 22, 3035–3045 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fischer, A. M., Katayama, C. D., Pages, G., Pouyssegur, J. & Hedrick, S. M. The role of Erk1 and Erk2 in multiple stages of T cell development. Immunity 23, 431–443 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Fusello, A. M. et al. The MAPK scaffold kinase suppressor of Ras is involved in ERK activation by stress and proinflammatory cytokines and induction of arthritis. J. Immunol. 177, 6152–6158 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Rincon, M. & Pedraza-Alva, G. JNK and p38 MAP kinases in CD4+ and CD8+ T cells. Immunol. Rev. 192, 131–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Dong, C., Davis, R. J. & Flavell, R. A. MAP kinases in the immune response. Annu. Rev. Immunol. 20, 55–72 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Yasuda, J., Whitmarsh, A. J., Cavanagh, J., Sharma, M. & Davis, R. J. The JIP group of mitogen-activated protein kinase scaffold proteins. Mol. Cell. Biol. 19, 7245–7254 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Willoughby, E. A., Perkins, G. R., Collins, M. K. & Whitmarsh, A. J. The JNK-interacting protein-1 scaffold protein targets MAPK phosphatase-7 to dephosphorylate JNK. J. Biol. Chem. 278, 10731–10736 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Verhey, K. J. et al. Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules. J. Cell Biol. 152, 959–970 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gallagher, E. et al. Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nature Immunol. 8, 57–63 (2007).

    Article  CAS  Google Scholar 

  47. Su, Y. C., Han, J., Xu, S., Cobb, M. & Skolnik, E. Y. NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J. 16, 1279–1290 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Matsuzawa, A. et al. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 321, 663–668 (2008). This paper proposes a two-step mechanism for signalling by CD40 in which a CD40-associated signalling complex that is scaffolded by MEKK1 must be released from the receptor into the cytoplasm for signal propagation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Blonska, M. et al. The CARMA1–Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway. Immunity 26, 55–66 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Lin, X. & Wang, D. The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling. Semin. Immunol. 16, 429–435 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Feske, S. Calcium signalling in lymphocyte activation and disease. Nature Rev. Immunol. 7, 690–702 (2007).

    Article  CAS  Google Scholar 

  52. Haase, H. et al. Ahnak is critical for cardiac Ca(v)1.2 calcium channel function and its β-adrenergic regulation. FASEB J. 19, 1969–1977 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Lee, I. H. et al. Ahnak protein activates protein kinase C (PKC) through dissociation of the PKC-protein phosphatase 2A complex. J. Biol. Chem. 283, 6312–6320 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Lee, I. H. et al. AHNAK-mediated activation of phospholipase C-γ1 through protein kinase C. J. Biol. Chem. 279, 26645–26653 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Matza, D. et al. A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation. Immunity 28, 64–74 (2008). This study establishes a role for AHNAK1 in calcium signalling in T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sekiya, F., Bae, Y. S., Jhon, D. Y., Hwang, S. C. & Rhee, S. G. AHNAK, a protein that binds and activates phospholipase C-γ1 in the presence of arachidonic acid. J. Biol. Chem. 274, 13900–13907 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Shiraishi-Yamaguchi, Y. & Furuichi, T. The Homer family proteins. Genome Biol. 8, 206 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Thomas, U. Modulation of synaptic signalling complexes by Homer proteins. J. Neurochem. 81, 407–413 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Xiao, B., Tu, J. C. & Worley, P. F. Homer: a link between neural activity and glutamate receptor function. Curr. Opin. Neurobiol. 10, 370–374 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Stiber, J. A. et al. Homer modulates NFAT-dependent signaling during muscle differentiation. Dev. Biol. 287, 213–224 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Huang, G. N. et al. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319, 476–481 (2008). This is the first study to show a role for HOMER proteins in calcium signalling in T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ninomiya-Tsuji, J. et al. The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398, 252–256 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Schauvliege, R., Janssens, S. & Beyaert, R. Pellino proteins: novel players in TLR and IL-1R signalling. J. Cell. Mol. Med. 11, 453–461 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Grosshans, J., Schnorrer, F. & Nusslein-Volhard, C. Oligomerisation of Tube and Pelle leads to nuclear localisation of dorsal. Mech. Dev. 81, 127–138 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Jiang, Z. et al. Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)–IRAK–tumor necrosis factor receptor-associated factor 6 (TRAF6) complex. J. Biol. Chem. 278, 10952–10956 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Yu, K. Y. et al. Cutting Edge: mouse pellino-2 modulates IL-1 and lipopolysaccharide signaling. J. Immunol. 169, 4075–4078 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Jensen, L. E. & Whitehead, A. S. Pellino3, a novel member of the Pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein. J. Immunol. 171, 1500–1506 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Liu, Y. et al. BCL10 mediates lipopolysaccharide/toll-like receptor-4 signaling through interaction with Pellino2. J. Biol. Chem. 279, 37436–37444 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Ting, J. P., Willingham, S. B. & Bergstralh, D. T. NLRs at the intersection of cell death and immunity. Nature Rev. Immunol. 8, 372–379 (2008).

    Article  CAS  Google Scholar 

  70. Martinon, F., Gaide, O., Petrilli, V., Mayor, A. & Tschopp, J. NALP inflammasomes: a central role in innate immunity. Semin. Immunopathol. 29, 213–229 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Petrilli, V., Dostert, C., Muruve, D. A. & Tschopp, J. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615–622 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Aganna, E. et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 46, 2445–2452 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Jin, Y. et al. NALP1 in vitiligo-associated multiple autoimmune disease. N. Engl. J. Med. 356, 1216–1225 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Eisenbarth, S. C., Colegio, O. R., O'Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bruey, J. M. et al. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 129, 45–56 (2007). This interesting study connects the NLRP1 inflammasome with the cell-death pathway and shows that anti-apoptotic molecules can inhibit the function of NLRP1.

    Article  CAS  PubMed  Google Scholar 

  76. Mayor, A., Martinon, F., De Smedt, T., Petrilli, V. & Tschopp, J. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nature Immunol. 8, 497–503 (2007).

    Article  CAS  Google Scholar 

  77. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Faustin, B. et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol. Cell 25, 713–724 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Hall, Z. W. & Sanes, J. R. Synaptic structure and development: the neuromuscular junction. Cell 72, S99–S121 (1993).

    Article  Google Scholar 

  80. Cemerski, S. & Shaw, A. Immune synapses in T-cell activation. Curr. Opin. Immunol. 18, 298–304 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Kennedy, M. B. Signal-processing machines at the postsynaptic density. Science 290, 750–754 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Gonzalez-Mariscal, L., Betanzos, A. & Avila-Flores, A. MAGUK proteins: structure and role in the tight junction. Semin. Cell Dev. Biol. 11, 315–324 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Kim, E. & Sheng, M. PDZ domain proteins of synapses. Nature Rev. Neurosci. 5, 771–781 (2004).

    Article  CAS  Google Scholar 

  84. Montgomery, J. M., Zamorano, P. L. & Garner, C. C. MAGUKs in synapse assembly and function: an emerging view. Cell. Mol. Life Sci. 61, 911–929 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Stephenson, L. M. et al. DLGH1 is a negative regulator of T-lymphocyte proliferation. Mol. Cell. Biol. 27, 7574–7581 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Xavier, R. et al. Discs large (Dlg1) complexes in lymphocyte activation. J. Cell Biol. 166, 173–178 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hanada, T., Lin, L., Chandy, K. G., Oh, S. S. & Chishti, A. H. Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes. J. Biol. Chem. 272, 26899–26904 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Round, J. L. et al. Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells. J. Exp. Med. 201, 419–430 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Round, J. L. et al. Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-κB transcription factors. Nature Immunol. 8, 154–161 (2007).

    Article  CAS  Google Scholar 

  90. Ashwell, J. D. The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nature Rev. Immunol. 6, 532–540 (2006).

    Article  CAS  Google Scholar 

  91. Yang, T. T., Xiong, Q., Enslen, H., Davis, R. J. & Chow, C. W. Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. Mol. Cell. Biol. 22, 3892–3904 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gomez del Arco, P., Martinez-Martinez, S., Maldonado, J. L., Ortega-Perez, I. & Redondo, J. M. A role for the p38 MAP kinase pathway in the nuclear shuttling of NFATp. J. Biol. Chem. 275, 13872–13878 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Wu, C. C., Hsu, S. C., Shih, H. M. & Lai, M. Z. Nuclear factor of activated T cells c is a target of p38 mitogen-activated protein kinase in T cells. Mol. Cell. Biol. 23, 6442–6454 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Cemerski, S. et al. The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse. Immunity 26, 345–355 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Krummel, M. F. & Macara, I. Maintenance and modulation of T cell polarity. Nature Immunol. 7, 1143–1149 (2006).

    Article  CAS  Google Scholar 

  96. Ludford-Menting, M. J. et al. A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation. Immunity 22, 737–748 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Allen, P. B., Ouimet, C. C. & Greengard, P. Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc. Natl Acad. Sci. USA 94, 9956–9961 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zito, K., Knott, G., Shepherd, G. M., Shenolikar, S. & Svoboda, K. Induction of spine growth and synapse formation by regulation of the spine actin cytoskeleton. Neuron 44, 321–334 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Sarrouilhe, D., di Tommaso, A., Metaye, T. & Ladeveze, V. Spinophilin: from partners to functions. Biochimie 88, 1099–1113 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Bloom, O. et al. Spinophilin participates in information transfer at immunological synapses. J. Cell Biol. 181, 203–211 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid, Saint Louis, Missouri 63110, USA.

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  1. Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid, Saint Louis, 63110, Missouri, USA

    Andrey S. Shaw & Erin L. Filbert

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Glossary

Immunological synapse

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

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

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

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

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

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

A molecular complex of several proteins that, once assembled, cleaves pro-IL-1β, thereby producing active IL-1β.

Vitiligo

A depigmenting disorder of the skin caused by the destruction of melanocytes, which produce cutaneous pigments.

Short hairpin RNA

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

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

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