Shedding Light on Cell-Cell Communication: An Optogenetic Study of Decision-Making in a Ras-to-STAT3 Delayed Signaling Circuit

Abstract

Each cell in the body receives and interprets signals from its neighbors and theenvironment. Sending the proper signal is a complex process, requiring a cell to bothsend signals quickly and at a high level that sufficiently acts on neighboring cells andlimit its own sensitivity. These cellular decisions should not be taken lightly because inthe busy, dynamic extracellular space, cells have to integrate information over time todecide if, how, and when to induce a tissue-wide response. Here, we study the logic ofthis decision-making process in cell-cell communication with the recently discoveredRas-to-STAT3 mammalian time-delayed paracrine circuit. Using an optogenetic (lightinducible)tool and high-resolution microscopy, we further characterized this circuit infiner time resolution. Interestingly, we found that sustained Ras signaling induces thesecretion of soluble STAT3-activating cytokines in a highly switch-like manner. Becausethe decision to secrete only occurs after 100 minutes of sustained Ras activation and theswitch resides at the level of secretion, but not protein synthesis, this implies thatsignaling is required early for the gradual production of STAT3-activating cytokines aswell as later for their subsequent secretion. Requiring early and late sustained signaling isindicative of a persistence detector, which was also supported by our resultsdemonstrating that transient Ras/Erk signals cannot activate STAT3. Finally, to enablefuture dissection of the Ras-to-secretion persistence detector, we identify IL-11 as thedominant Ras-dependent cytokine and demonstrate that this circuit is observed acrossdifferent cell types. Taken together, our results implicate the Ras-to-STAT3 delayedsignaling circuit as disease-relevant model system that connects cellular interpretation oftime-varying signals to decisions made in cell-cell communication.