Abstract
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, PLCγ1, which assembles in response to receptor phosphorylation. SHP2 and activated PLCγ1 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 PLCγ1 to facilitate access to its plasma membrane substrate. Thus, LLPS modulates RTK signaling, with potential consequences for therapeutic intervention.
Original language | English (US) |
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Pages (from-to) | 1089-1106.e12 |
Journal | Molecular cell |
Volume | 82 |
Issue number | 6 |
DOIs | |
State | Published - Mar 17 2022 |
Keywords
- FGFR2
- kinase activity
- Liquid-liquid phase separation (LLPS)
- phosphatase activity
- phospholipase activity
- Plcγ1
- Receptor tyrosine kinases (RTKs)
- Shp2
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology