Phase separation of signaling molecules promotes T cell receptor signal transduction

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Science  29 Apr 2016:
Vol. 352, Issue 6285, pp. 595-599
DOI: 10.1126/science.aad9964

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Phase separation organizes signaling

In T cell receptors, signaling molecules reorganize into tiny phase-separated droplets—like oil in water. Su et al. used an in vitro system with artificial membranes and 12 components of the T cell receptor signaling system to closely monitor the role of these molecular clusters (see the Perspective by Dustin and Muller). The clusters formed through phosphorylation-dependent association of the linker protein LAT (linker for activation of T cells) with other proteins. These clusters also managed to exclude an inactivating phosphatase and increased the specific activity of enzymes controlling actin polymerization.

Science, this issue p. 595; see also p. 516


Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer- or submicrometer-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.

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