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Spatial organization and signal transduction at intercellular junctions

Nature Reviews Molecular Cell Biology volume 11, pages 342–352 (2010)Cite this article

Subjects

Key Points

  • In juxtacrine signalling, surfaces of interacting cells come into direct contact and receptor–ligand recognition at this interface triggers intracellular signalling. Interactions involve multiple adhesion and signalling molecules, the collective behaviour of which regulates signal transduction.

  • The coordinated organization of cell membrane receptors into micrometre-scale patterns is emerging as a broadly significant theme of intercellular signalling, as exemplified by immunological synapses. Recent evidence suggests that this dynamic spatial organization has an active role in regulating the signalling state of individual molecular components and thus can alter long-term cell activation.

  • The physical mechanisms that establish and regulate the spatial organization of signalling molecules are equally as important as the chemical reactions themselves and both the cell membrane and the actin cytoskeleton have key roles.

  • The role of spatial organization is best appreciated by experiments that physically alter the organization of cell surface molecules at the interface between two cells. As a result, new experimental strategies have emerged to manipulate the spatial organization of molecules inside living cells.

Abstract

The coordinated organization of cell membrane receptors into diverse micrometre-scale spatial patterns is emerging as an important theme of intercellular signalling, as exemplified by immunological synapses. Key characteristics of these patterns are that they transcend direct protein–protein interactions, emerge transiently and modulate signal transduction. Such cooperativity over multiple length scales presents new and intriguing challenges for the study and ultimate understanding of cellular signalling. As a result, new experimental strategies have emerged to manipulate the spatial organization of molecules inside living cells. The resulting spatial mutations yield insights into the interweaving of the spatial, mechanical and chemical aspects of intercellular signalling.

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Figure 1: Micrometre-scale protein patterns in the immunological synapse.
Figure 2: Signalling states are location-dependent in the immunological synapse.
Figure 3: Spatial organization influences cell signalling in the immunological synapse.
Figure 4: Cellular mechanisms controlling spatial organization in intercellular junctions.
Figure 5: Experimental manipulation of spatial organization in intercellular junctions.
Figure 6: Immunological synapse spatial mutations.

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Acknowledgements

The hybrid live cell–supported membrane component of this work was supported by the Director, Office of Science, Office of Basic Energy Sciences, Chemical Sciences, Geosciences and Biosciences Division of the U.S. Department of Energy under contract number DE-AC02-05CH11231. General support for this project was also provided by a National Science Foundation CAREER award MCB-0448614 to J.T.G.

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Authors and Affiliations

  1. Department of Chemistry, Howard Hughes Medical Institute, University of California, Berkeley, 94720, California, USA

    Boryana N. Manz & Jay T. Groves

  2. and Physical Biosciences and Materials Sciences Divisions, Biophysics Graduate Group, Lawrence Berkeley National Lab, Berkeley, 94720, California, USA

    Boryana N. Manz & Jay T. Groves

  3. Physical Biosciences and Materials Sciences Divisions, Lawrence Berkeley National Lab, Berkeley, 94720, California, USA

    Jay T. Groves

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Glossary

Cytokine

A member of a large family of immunomodulating secreted proteins that interact with cellular receptors. Cytokine production results in the activation of an intracellular signalling cascade that commonly regulates processes such as inflammation.

Miscibility phase separation

The partitioning of lipid components (in the context of membranes) into domains that have different chemical compositions and physical properties.

LAT

(Linker for activation of T cells). A transmembrane protein that on TCR activation becomes rapidly phosphorylated and binds multiple adaptor molecules and indirectly recruits others.

hsPALM

(High speed photoactivated localization microscopy). A fluorescence imaging technique in which sequential activation, localization and bleaching of fluorescent reporter proteins yields an image with a resolution of a few tens of nanometers, well below the diffraction limit.

dcFFCS

(Dual colour fluorescence cross-correlation spectroscopy). A technique that analyses the dynamics and association of two different diffusing fluorescent proteins.

Chemotaxis

Directed cell movement according to chemical stimuli.

Liposome or proteoliposome

A vesicle made of lipid bilayer in an aqueous environment. Membrane proteins can be incorporated in the bilayer.

Photo-switchable molecule

A molecule with a functionality (ligand binding, conformational change or absorption spectrum) that is controlled by light and in some cases can be toggled on and off.

Uncaging

The light-controlled release of a functional group that hides (cages) another functional group.

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Manz, B., Groves, J. Spatial organization and signal transduction at intercellular junctions. Nat Rev Mol Cell Biol 11, 342–352 (2010). https://doi.org/10.1038/nrm2883

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