Spatial organization and signal transduction at intercellular junctions

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.Cell-to-cell communication is mediated by various methods. Endocrine signals are secreted and reach distant target cells, paracrine signals are secreted and reach targets in the vicinity, and autocrine signals are secreted and received by the same cell. By contrast, in juxtacrine signalling, surfaces of interacting cells come into direct contact and receptor-ligand recognition at this interface triggers intracellular signalling. Cell-cell interactions involve multiple adhesion and signalling molecules, the collective behaviour of which regulates signal transduction 1 . Also intrinsic to juxtacrine signalling configurations are large physical constraints on molecular movement and assembly. Genetic and biochemical approaches have been invaluable in identifying the molecular components of signal transduction pathways in juxtacrine signalling and in characterizing the biochemical interactions among them. Despite this wealth of information, in many cases it remains impossible to describe the behaviour of a signalling system in terms of the individual molecular properties of its components. Protein-protein inter actions and the formation of molecular clusters are widely implicated in signal transduction and contribute to a first level of cooperativity [2][3][4] . Recently, the coordinated organization of cell membrane receptors into micrometre-scale patterns has emerged as a broadly important theme of intercellular signalling 1,[5][6][7][8][9] .A paradigm for the interplay of spatial patterns and signal transduction is the junction between T cells and their target cells, termed the immunological synapse [8][9][10][11][12][13] . Spatial HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscriptpatterns of proteins at the cell-cell interface develop as hundreds of receptors recognize their cognate ligands on the apposed cell membrane. Multiple signalling and adhesion molecules also become organized into distinctive spatial patterns at the interface between the two cells 8,9,13,14 (FIG. 1). The patterns create long-range interactions and seem to have specific purposes in signal transduction 8,9 . They host the local enrichment or depletion of key signalling components, which can bias biochemical cascades towards different functional o...

Molecular mechanisms in signal transduction at the membrane

“…Importantly, the basic combination of properties that lead to this behavior is not so difficult to achieve, suggesting that dynamic spatial organization could be involved in a wide range of signaling processes. Indeed, similar wave patterns of actin polymerization can be observed along the membranes of eukaryotic cells 15 .More complex membrane surface effects arise in juxtacrine signaling, in which both ligand and receptor reside in apposed membranes 16,17 . In two recent studies, the binding kinetics between T-cell receptors (TCRs) and their peptide major histocompatibility complex (pMHC) ligands was measured in situ by single-molecule microscopy and Förster resonance It is clear that the membrane is not a homogeneous fluid.…”

“…More complex membrane surface effects arise in juxtacrine signaling, in which both ligand and receptor reside in apposed membranes 16,17 . In two recent studies, the binding kinetics between T-cell receptors (TCRs) and their peptide major histocompatibility complex (pMHC) ligands was measured in situ by single-molecule microscopy and Förster resonance energy transfer (FRET) 18 and by direct mechanical assays 19 .…”

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

“…Receptor clustering is dependent on many aspects, such as ligand affinity, ligand dissociation, the size of ligands, and the concentration of coactivators (63)(64)(65)(66). In the case of the B cell receptor and T cell receptor clusters, the mobility of the ligand also affects the clustering of these receptors (67,68).…”

Three-dimensional manipulation of single cells using surface acoustic waves

“…In addition, we expect this technology to rebuild the 3D architecture of a tumor, which will aid in the investigation of heterogeneous genetic alterations during tumor growth and metastasis process (22). The ability to precisely transport single cells along three axes using our 3D acoustic tweezers may facilitate investigations of a number of challenging problems in biology, particularly those involved in the spatial regulation of cells in 2D or 3D environments (23).…”