PerspectiveCell Signaling

Dwelling at membranes promotes decisive signaling

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Science  08 Mar 2019:
Vol. 363, Issue 6431, pp. 1036-1037
DOI: 10.1126/science.aaw6434

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Summary

Transmission of signals from external stimuli into the interior of cells relies on complex signaling pathways that must be efficient and precise—every facet of life depends on this. Cells use biomolecular interactions in signaling pathways to make crucial decisions about whether to transmit signals or filter them out as noise. How is this possible, given that biomolecular interactions are inherently stochastic processes? The activation of membrane receptors typically involves the phosphorylation of their intracellular domain and subsequent recruitment of adaptor molecules and downstream effectors. The effectors amplify the original signal by catalyzing a reaction. Dozens of signaling pathways adhere to these principles, and they lead to decisive cellular responses without false-positive activation. How do they prevent activation due to spontaneous partial phosphorylation of receptors? On pages 1093 and 1098 of this issue, Case et al. (1) and Huang et al. (2), respectively, report that multivalent interactions between membrane receptors and downstream adaptor molecules lead to clustering and can induce phase transitions in which the receptor-adaptor complexes separate from the bulk solution and form a viscous dense phase at the membrane. As a consequence, the residence time, or dwell time, of effectors is dramatically increased at the membrane. Given that activation of effectors is typically slow, these long dwell times increase the likelihood of activation. By contrast, short dwell times of effectors recruited to unclustered receptors are much less likely to result in activation. These observations are relevant for a large class of membrane receptors and reveal the fundamental molecular mechanism of sensitive, specific signal transduction into the cell.

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