Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state

The recruitment of signaling proteins into activated receptor tyrosine kinases (RTKs) to produce rapid, high-fidelity downstream response is exposed to the ambiguity of random diffusion to the target site. Liquid-liquid phase separation (LLPS) overcomes this by providing elevated, localized concentrations of the required proteins while impeding competitor ligands. Here, we show a subset of phosphorylation-dependent RTK-mediated LLPS states. We then investigate the formation of phase-separated droplets comprising a ternary complex including the RTK, (FGFR2); the phosphatase, SHP2; and the phospholipase, PLC gamma 1, which assembles in response to receptor phosphorylation. SHP2 and activated PLC gamma 1 interact through their tandem SH2 domains via a previously undescribed interface. The complex of FGFR2 and SHP2 combines kinase and phosphatase activities to control the phosphorylation state of the assembly while providing a scaffold for active PLC gamma 1 to facilitate access to its plasma membrane substrate. Thus, LLPS modulates RTK signaling, with potential consequences for therapeutic intervention.

Automated summary

This study reveals a state of liquid-liquid phase separation that brings activated receptor tyrosine kinases (RTKs) to localized high concentrations of required proteins, overcoming the ambiguity of random diffusion. The study also discovers the formation process of phase-separated droplets comprising a ternary complex including RTK, phosphatase SHP2, and phospholipase PLC gamma 1, and identifies a previously undescribed interface. The complex combines kinase and phosphatase activities to control phosphorylation state and provides a scaffold for active PLC gamma 1 to facilitate access to its plasma membrane substrate. Thus, liquid-liquid phase separation modulates RTK signaling with potential consequences for therapeutic intervention.